ES2250177T3 - HETEROPOLICICLIC COMPOUNDS AND THEIR USE AS ANTAGONISTS OF METABOTROPIC GLUTAMATE RECEPTORS. - Google Patents

HETEROPOLICICLIC COMPOUNDS AND THEIR USE AS ANTAGONISTS OF METABOTROPIC GLUTAMATE RECEPTORS.

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ES2250177T3
ES2250177T3 ES00955657T ES00955657T ES2250177T3 ES 2250177 T3 ES2250177 T3 ES 2250177T3 ES 00955657 T ES00955657 T ES 00955657T ES 00955657 T ES00955657 T ES 00955657T ES 2250177 T3 ES2250177 T3 ES 2250177T3
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pyridyl
oxazole
oxadiazole
cyanophenyl
chloro
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Bradford C. Van Wagenen
Thomas M. Stormann
Scott T. Moe
Susan M. Sheehan
Donald A. Mcleod
Daryl L. Smith
Methvin Benjamin Isaac
Abdelmalik Slassi
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Shire NPS Pharmaceuticals Inc
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Abstract

Un compuesto seleccionado de a) un compuesto de **fórmula**en el que X e Y son N, Z es O; Ar1 es 2-piridilo y Ar2 es fenilo, en el que al menos uno de los restos Ar1 y Ar2 se sustituye con uno o más restos seleccionados del grupo que consta de ¿F, -Cl, -Br, -I, - SR, -SOR, -SO2R, -SO2NRR¿, -OCOR, -OCONRR¿, -NRCOR¿, - NRCO2R¿, -CN, -CO2R, -CONRR¿, -C(O)R, -CH(OR)R¿, -CH2(OR), y ¿R; en el que R o R¿ se selecciona del grupo que consta de H, CF3, alquilo(C1-C10), cicloalquilo, alquilarilo, heterocicloalquilo, arilo y donde R y R¿ pueden combinarse para formar un anillo, con la condición de que el compuesto no sea 3-(2- piridil)-5-(2-clorofenil)-1, 2, 4-oxadiazol, 3-(2-piridil)-5- fenil-1, 3, 4-oxadiazol, o 3-(2-piridil)-5-[3- (trifluorometil)fenil]-1, 24-oxadiazol; o b) 3-(2-piridil)-5-[3-(trifluorometoxi)fenil]-1, 2, 4- oxadiazol, 3-(2-piridil)-5-(2, 3-difluorofenil)-1, 2, 4- oxadiazol, 3-(2-piridil)-5-(3, 5-dimetoxifenil)-1, 2, 4- oxadiazol, 3-(5-fluoropirid-2-il)-5-(3, 5-dimetoxifenil)-1, 2, 4- oxadiazol, 3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1, 2, 4- oxadiazol, 3-(2-piridil)-5-(3-nitrofenil)-1, 2, 4-oxadiazol, 2-[3-clorofenil]-4-[piridin-2-il]-1, 3-oxazol, o una sal farmacéuticamente aceptable de los mismos.A compound selected from a) a compound of ** formula ** in which X and Y are N, Z is O; Ar1 is 2-pyridyl and Ar2 is phenyl, in which at least one of the residues Ar1 and Ar2 is substituted with one or more residues selected from the group consisting of ¿F, -Cl, -Br, -I, - SR, -SOR, -SO2R, -SO2NRR¿, -OCOR, -OCONRR¿, -NRCOR¿, - NRCO2R¿, -CN, -CO2R, -CONRR¿, -C (O) R, -CH (OR) R¿, -CH2 (OR), and ¿R; wherein R or R ¿is selected from the group consisting of H, CF3, (C1-C10) alkyl, cycloalkyl, alkylaryl, heterocycloalkyl, aryl and where R and R¿ can be combined to form a ring, with the proviso that the compound is not 3- (2- pyridyl) -5- (2-chlorophenyl) -1, 2, 4-oxadiazole, 3- (2-pyridyl) -5-phenyl-1, 3, 4-oxadiazole, or 3 - (2-pyridyl) -5- [3- (trifluoromethyl) phenyl] -1,24-oxadiazole; ob) 3- (2-pyridyl) -5- [3- (trifluoromethoxy) phenyl] -1, 2, 4- oxadiazol, 3- (2-pyridyl) -5- (2, 3-difluorophenyl) -1, 2 , 4- oxadiazol, 3- (2-pyridyl) -5- (3, 5-dimethoxyphenyl) -1, 2, 4- oxadiazol, 3- (5-fluoropyrid-2-yl) -5- (3, 5- dimethoxyphenyl) -1, 2, 4- oxadiazole, 3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1, 2, 4- oxadiazole, 3- (2-pyridyl) -5- ( 3-nitrophenyl) -1, 2, 4-oxadiazole, 2- [3-chlorophenyl] -4- [pyridin-2-yl] -1, 3-oxazole, or a pharmaceutically acceptable salt thereof.

Description

Compuestos heteropolicíclicos y su uso como antagonistas de receptores de glutamato metabotrópico.Heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists.

Campo de la invenciónField of the Invention

La invención proporciona compuestos activos como receptores metabotrópicos de glutamato y que son útiles para tratar enfermedades y trastornos neurológicos y psiquiátricos.The invention provides active compounds such as metabotropic glutamate receptors and which are useful for treating neurological and psychiatric diseases and disorders.

Antecedentes de la invenciónBackground of the invention

Avances recientes en la elucidación de los papeles neurofisiológicos de los receptores metabotrópicos de glutamato han establecido a estos receptores como dianas de fármacos prometedoras en la terapia de trastornos y enfermedades agudos o crónicos neurológicos y psiquiátricos. Sin embargo, el principal reto para la realización de esta promesa ha sido el desarrollo de compuestos selectivos de subtipo de receptor de glutamato metabotrópico.Recent advances in the elucidation of neurophysiological roles of metabotropic receptors of glutamate have established these receptors as drug targets promising in the therapy of acute disorders and diseases or Chronic neurological and psychiatric. However, the main challenge for the realization of this promise has been the development of selective glutamate receptor subtype compounds metabotropic

El glutamato es el principal neurotransmisor excitador en el sistema nervioso central (SNC) de los mamíferos. El glutamato produce sus efectos en neuronas centrales uniendo a y por lo tanto activando receptores de superficie celular. Estos receptores de ha dividido en dos clases principales, los receptores de glutamato ionotrópicos y los metabotrópicos, basados en las características estructurales de las proteínas receptoras, los medios por los cuales los receptores transducen señales dentro de la célula, y perfiles farmacológicos.Glutamate is the main neurotransmitter exciter in the central nervous system (CNS) of mammals. He glutamate produces its effects on central neurons joining and by thus activating cell surface receptors. These receptors has divided into two main classes, the receptors of ionotropic and metabotropic glutamate, based on structural characteristics of the receptor proteins, the means by which receivers transduce signals within the cell, and pharmacological profiles.

Los receptores de glutamato metabotrópicos (mGluR) son receptores acoplados a proteínas G que activan una diversidad de sistemas segundos mensajeros intracelulares que siguen a la unión de glutamato. La activación de mGluR en neuronas de mamífero intactas facilita una o más de las siguientes respuestas: activación de fosfolipasa C; incrementos en hidrólisis de fosfoinosítido (PI); liberación intracelular de calcio; activación de fosfolipasa D; activación o inhibición de adenilciclasa; incrementos o decrementos en la formación de adenosín monofosfato cíclico (AMPc); activación de guanidil ciclasa, incrementos en la formación de guanosín monofosfato cíclico (GMPc); activación de fosfolipasa A; incrementos en liberación de ácido araquidónico; e incrementos o decrementos en la actividad de canales iónicos que se abren por voltaje o que se abren por ligando. Schoepp y col., Trends. Pharmacol. Sci. 14:13 (1993); Schoepp, Neurochem. Int. 24:439 (1994); Pin y col., Neuropharmacology 34:1 (1995).Metabotropic glutamate receptors (mGluR) are G-protein coupled receptors that activate a variety of intracellular second messenger systems that follow glutamate binding. Activation of mGluR in intact mammalian neurons facilitates one or more of the following responses: phospholipase C activation; increases in phosphoinositide (PI) hydrolysis; intracellular calcium release; phospholipase D activation; activation or inhibition of adenyl cyclase; increases or decreases in the formation of cyclic adenosine monophosphate (cAMP); guanidyl cyclase activation, increases in the formation of cyclic guanosine monophosphate (cGMP); phospholipase A activation; increases in arachidonic acid release; and increases or decreases in the activity of ion channels that open by voltage or that open by ligand. Schoepp et al., Trends. Pharmacol Sci. 14 : 13 (1993); Schoepp, Neurochem. Int. 24 : 439 (1994); Pin et al., Neuropharmacology 34 : 1 (1995).

Se han identificado mediante clonado molecular ocho subtipos distintos de mGluR, llamados de mGluR1 a
mGluR8. Véase, por ejemplo, Nakatishi, Neuron 13:1031 (1994); Pin y col., Neuropharmacology 34:1 (1995); Knopfel y col., J. Med. Chem. 38:1417 (1995). La diversidad del receptor adicional que ocurre por medio de la expresión de formas que proceden de "splicing" alternativo de ciertos subtipos de mGluR. Pin y col., PNAS 89:10331 (1992); Minakami y col., BBRC 199:1136 (1994); Joly y col., J. Neurosci. 15:3970 (1995).Eight different subtypes of mGluR have been identified by molecular cloning, called mGluR1 a
mGluR8. See, for example, Nakatishi, Neuron 13 : 1031 (1994); Pin et al., Neuropharmacology 34 : 1 (1995); Knopfel et al., J. Med. Chem. 38 : 1417 (1995). The diversity of the additional receptor that occurs through the expression of forms that come from alternative "splicing" of certain subtypes of mGluR. Pin et al., PNAS 89 : 10331 (1992); Minakami et al., BBRC 199 : 1136 (1994); Joly et al., J. Neurosci . 15: 3970 (1995).

Los subtipos del receptor de glutamato metabotrópico se pueden subdividir en tres grupos, mGluR de Grupo I, mGluR de Grupo II, y mGluR de Grupo III, basados en homología de secuencia de aminoácidos, los sistemas del segundo mensajero utilizados por los receptores, y por sus características farmacológicas. Nakanishi, Neuron 13:1031 (1994); Pin y col., Neuropharmacology 34:1 (1995); Knopfel y col., J. Med. Chem 38:1417 (1995).Subtypes of the metabotropic glutamate receptor can be subdivided into three groups, mGluR Group I, mGluR Group II, and mGluR Group III, based on amino acid sequence homology, second messenger systems used by the recipients, and by Its pharmacological characteristics. Nakanishi, Neuron 13 : 1031 (1994); Pin et al., Neuropharmacology 34 : 1 (1995); Knopfel et al., J. Med. Chem 38: 1417 (1995).

El grupo I de mGluR comprende mGluR1, mGluR5, y sus variantes procedentes de "splicing" alternativos. La unión de agonistas a estos receptores da como resultado la activación de fosfolipasa C y la subsiguiente movilización de calcio intracelular. Las medidas electrofisiológicas se pueden usar para demostrar estos efectos, por ejemplo en los oocitos de Xenophus que expresan receptores mGluR1 recombinantes. Véase, por ejemplo, Masu y col., Nature 349:760 (1991): Pin y col., PNAS 89:10331 (1992). Se han conseguido resultados similares con oocitos que expresan receptores mGluR5 recombinantes. Abe y col., J. Biol. Chem. 267:13361 (1992); Minakami y col., BBRC 199:1136 (1994); Joly y col., J. Neurosci 15:3970 (1995). Alternativamente, la activación de agonistas de receptores de mGluR1 recombinantes expresados en células de ovario de hámster chino (CHO) estimula hidrólisis de PI, formación de AMPc, y liberación de ácido araquidónico como se mide mediante los ensayos bioquímicos estándar. Aramori y col., Neuron 8:757 (1992).Group I of mGluR comprises mGluR1, mGluR5, and their alternative splicing variants. The binding of agonists to these receptors results in the activation of phospholipase C and the subsequent mobilization of intracellular calcium. Electrophysiological measurements can be used to demonstrate these effects, for example in Xenophus oocytes that express recombinant mGluR1 receptors. See, for example, Masu et al., Nature 349: 760 (1991): Pin et al., PNAS 89 : 10331 (1992). Similar results have been achieved with oocytes expressing recombinant mGluR5 receptors. Abe et al., J. Biol. Chem. 267 : 13361 (1992); Minakami et al., BBRC 199 : 1136 (1994); Joly et al., J. Neurosci 15 : 3970 (1995). Alternatively, the activation of recombinant mGluR1 receptor agonists expressed in Chinese hamster ovary (CHO) cells stimulates PI hydrolysis, cAMP formation, and arachidonic acid release as measured by standard biochemical assays. Aramori et al., Neuron 8 : 757 (1992).

Por comparación, la activación de los receptores mGluR5, expresados en células CHO, estimula la hidrólisis de PI y los intermedios de calcio intracelulares, pero no se observa ninguna estimulación de formación de cAMP o liberación de ácido araquidónico. Abe y col., J. Biol. Chem. 267:13361 (1992). Sin embargo, la activación de receptores mGluR5 expresados en células LLC-PK1 dan como resultado hidrólisis de PI y formación de AMPc incrementada. Joly y col., J. Neurosci 15:3970 (1995). El perfil de la potencia de agonista para mGluR es quiscualato > glutamato = ibotenato > (2S, 1'S, 2'S)-2-carboxiciclopropilglicina (L-CCG-I) > ácido (1S,3R)-1-aminociclopentano-1,3-dicarboxílico (ACPD). El quiscualato es relativamente selectivo para receptores del grupo I, comparados con los mGluR del Grupo II y el Grupo III, pero también es un potente activador de receptores ionotrópicos AMPA. Pin y col., Neuropharmacology 34:1, Knopfel y col., J. Med. Chem. 38:1417 (1995).By comparison, the activation of mGluR5 receptors, expressed in CHO cells, stimulates the hydrolysis of PI and intracellular calcium intermediates, but no stimulation of cAMP formation or arachidonic acid release is observed. Abe et al., J. Biol. Chem. 267 : 13361 (1992). However, activation of mGluR5 receptors expressed in LLC-PK1 cells results in PI hydrolysis and increased cAMP formation. Joly et al., J. Neurosci 15 : 3970 (1995). The agonist potency profile for mGluR is cyclocuate> glutamate = ibotenate> (2S, 1'S, 2'S) - 2-carboxycyclopropylglycine (L-CCG-I)> acid (1S, 3R) -1-aminocyclopentane-1,3 dicarboxylic (ACPD). The qucuacuate is relatively selective for Group I receptors, compared to Group II and Group III mGluRs, but it is also a potent activator of AMPA ionotropic receptors. Pin et al., Neuropharmacology 34 : 1, Knopfel et al., J. Med. Chem. 38 : 1417 (1995).

La carencia de agonistas y antagonistas de mGluR específicos de subtipo ha impedido la elucidación de los papeles fisiológicos en los mGluRs particulares, y los procesos patofisiológicos asociados a GluR que afectan al SNC tienen aún que definirse. Sin embargo, trabajar con los agonistas y antagonistas no específicos disponibles ha producido algu-
nos entendimientos generales sobre los mGluR del Grupo I comparados con los mGluR del Grupo II y del Grupo III.The lack of subtype-specific mGluR agonists and antagonists has prevented elucidation of physiological roles in particular mGluRs, and the pathophysiological processes associated with GluR that affect the CNS have yet to be defined. However, working with the available nonspecific agonists and antagonists has produced some
General understandings about Group I mGluRs compared to Group II and Group III mGluRs.

Intentos de elucidar los papeles fisiológicos de los mGluR del Grupos I sugieren que la activación de estos receptores facilitan la excitación neuronal. Diversos estudios han demostrado que APCD puede producir excitación postsináptica en la aplicación a neuronas en el hipocampo, córtex cerebral, cerebelo, y tálamo, igual que otras regiones cerebrales. La evidencia indica que esta excitación se debe a la activación directa de mGluR postsinápticos, pero se ha sugerido también que la activación de mGluR presinápticos tiene lugar, dando como resultado liberación de neutoransformado ácido. Baskys, Trends Pharmacol. Sci. 15:92 (1992); Schoepp, Neurochem. Int. 24:439 (1994); Pin y col., Neuropharmacology 34:1 (1995).Attempts to elucidate the physiological roles of Group I mGluRs suggest that the activation of these receptors facilitates neuronal excitation. Several studies have shown that APCD can produce postsynaptic excitation in the application to neurons in the hippocampus, cerebral cortex, cerebellum, and thalamus, just like other brain regions. Evidence indicates that this excitation is due to the direct activation of postsynaptic mGluRs, but it has also been suggested that activation of presynaptic mGluRs takes place, resulting in the release of acid-transformed neo-transforms. Baskys, Trends Pharmacol. Sci. 15 : 92 (1992); Schoepp, Neurochem. Int. 24 : 439 (1994); Pin et al., Neuropharmacology 34 : 1 (1995).

Los experimentos farmacológicos implican mGluR del Grupo I como los mediadores de este mecanismo excitados. Los efectos de ACPD se pueden reproducir mediante concentraciones bajas de quiscualato en la presencia de antagonistas iGluR. Hu y col., Brain Res. 568:339 (1991); Greene y col., Eur. J. Pharmacol. 226:279 (1992). Dos compuestos de fenilglicina conocidos por activar mGluR1, a saber (S)-3-hidroxifenilglicina ((S)-3HPG) y (S)-3,5-dihidroxifenilglicina ((S)-DHPG), produce también excitación. Watkins y col., Trends Pharmacol. Sci. 15:33 (1994). Además, la excitación se puede bloquear mediante (S)-4-carboxifenilglicina ((S)-4CPG), (S)-4-carboxi-3-hidroxifenilglicina ((S)-4C3HPG), y (+)-alfa-metil-4-carboxifenilglicina ((+)-MCPG), compuestos conocidos por ser antagonistas de mGluR1. Eaton y col., Eur. J. Pharmacol. 244:195 (1993); Watkins y col., Trends Pharmacol. Sci. 15:333 (1994).Pharmacological experiments involve Group I mGluR as the mediators of this excited mechanism. The effects of ACPD can be reproduced by low concentrations of qucuacuate in the presence of iGluR antagonists. Hu et al., Brain Res. 568 : 339 (1991); Greene et al., Eur. J. Pharmacol. 226 : 279 (1992). Two phenylglycine compounds known to activate mGluR1, namely (S) -3-hydroxyphenylglycine ( (S) -3HPG) and (S) -3,5-dihydroxyphenylglycine ( (S) -DHPG), also produces excitation. Watkins et al., Trends Pharmacol. Sci. 15:33 (1994). In addition, the excitation can be blocked by (S) -4-carboxyphenylglycine ( (S) -4CPG), (S) -4-carboxy-3-hydroxyphenylglycine ( (S) -4C3HPG), and (+) - alpha-methyl -4-carboxyphenylglycine ((+) - MCPG), compounds known to be antagonists of mGluR1. Eaton et al., Eur. J. Pharmacol. 244 : 195 (1993); Watkins et al., Trends Pharmacol. Sci. 15 : 333 (1994).

Receptores de glutamato metabotrópicos se han implicado en un número de procedimientos normales en el SNC de mamíferos. La activación de mGluRs ha mostrado requerirse para inducción de potenciación a largo plazo hipocámpica y depresión a largo plazo cerebelar. Bashir, y col., Nature 363:347 (1993); Bortolotto y col, Nature 368:740 (1994); Aiba y col., Cell 79:365 (1994); Aiba y col., Cell 79:377 (1994). Se ha demostrado un papel para la activación de mGluR en nocicepción y analgesia. Meller y col., Neuroreport 4: 879 (1993). Además, la activación de mGluR se ha sugerido que juega un papel modulador en una diversidad de otros procedimientos normales que incluyen transmisiones sinápticas, desarrollo neuronal, muerte celular apoptótica, plasticidad sináptica, aprendizaje espacial, memoria olfativa, control central de actividad cardiaca, despertar, control motor, y control del reflejo vestíbulo-ocular. En general, véase Nakanishi, Neuron 13: 1031 (1994); Pin y col., Neuropharmacology 34:1 (1995); Knopfel y col., J. Med. Chem. 38:1417 (1995).Metabotropic glutamate receptors have been implicated in a number of normal procedures in the mammalian CNS. The activation of mGluRs has been shown to be required for induction of hypocampic long-term potentiation and cerebellar long-term depression. Bashir, et al., Nature 363 : 347 (1993); Bortolotto et al, Nature 368 : 740 (1994); Aiba et al., Cell 79 : 365 (1994); Aiba et al., Cell 79 : 377 (1994). A role for the activation of mGluR in nociception and analgesia has been demonstrated. Meller et al., Neuroreport 4 : 879 (1993). In addition, mGluR activation has been suggested to play a modulating role in a variety of other normal procedures that include synaptic transmissions, neuronal development, apoptotic cell death, synaptic plasticity, spatial learning, olfactory memory, central control of cardiac activity, awakening, motor control, and control of the vestibule-ocular reflex. In general, see Nakanishi, Neuron 13 : 1031 (1994); Pin et al., Neuropharmacology 34 : 1 (1995); Knopfel et al., J. Med. Chem. 38 : 1417 (1995).

Los receptores de glutamato metabotrópicos se han sugerido también para jugar papeles en una diversidad de procesos patofisiológicos y estados morbosos que afectan al SNC. Estos incluyen apoplejía, traumatismo en la cabeza, daños anóxicos e isquémicos, hipoglicemia, epilepsia, y enfermedades neurodegenerativas tales como enfermedad de Alzheimer. Schoepp y col., Trends. Pharmacol. Sci. 14:13 (1993); Cunningham y col., Life Sci. 54:135 (1994); Hollman y col., Ann. Rev. Neurosci. 17:31 (1994); Pin y col., Neuropharmacology 34:1 (1995); Knopfel y col., J. Med. Chem. 38:1417 (1995). Muchas de las patologías en estas condiciones se cree que se deben a excesiva excitación inducida por glutamato de las neuronas del SNC. Debido a que el Grupo I de mGluR parece incrementar la excitación neuronal mediada por glutamato por medio de mecanismos postsinápticos y liberación de glutamato presináptica potenciada, su activación probablemente contribuye a la patología. De acuerdo con ello, los antagonistas selectivos de los receptores del Grupo I de mGluR pueden ser beneficiosos terapéuticamente, específicamente como agentes neuroprotectores, analgésicos, o anticonvulsivantes.Metabotropic glutamate receptors have also been suggested to play roles in a variety of pathophysiological processes and morbid conditions that affect the CNS. These include stroke, head trauma, anoxic and ischemic damage, hypoglycemia, epilepsy, and neurodegenerative diseases such as Alzheimer's disease. Schoepp et al., Trends. Pharmacol Sci. 14 : 13 (1993); Cunningham et al., Life Sci . 54: 135 (1994); Hollman et al., Ann. Rev. Neurosci . 17:31 (1994); Pin et al., Neuropharmacology 34 : 1 (1995); Knopfel et al., J. Med. Chem. 38 : 1417 (1995). Many of the pathologies in these conditions are believed to be due to excessive glutamate-induced excitation of CNS neurons. Because mGluR Group I appears to increase glutamate-mediated neuronal excitation through postsynaptic mechanisms and enhanced presynaptic glutamate release, its activation probably contributes to the pathology. Accordingly, selective antagonists of mGluR Group I receptors can be therapeutically beneficial, specifically as neuroprotective, analgesic, or anticonvulsant agents.

Los estudios preliminares que valoran los potenciales terapéuticos con los agonistas y antagonistas de mGluR disponibles han producido aparentemente resultados contradictorios. Por ejemplo, se ha comunicado que la aplicación de APCD sobre las neuronas hipocámpicas conduce a ataques de apoplejía y daños neuronales (Sacaan y col., Neurosci. Lett. 139:77 (1992); Lipparti y col., Life Sci. 52:85 (1993). Otros estudios indican, sin embargo, que ACPD inhibe la actividad epileptiforme, y puede también presentar propiedades neuroprotectoras. Taschenberger y col., Neuroreport 3:629 (1992); Sheardown, Neuroreport 3:916 (1992); Koh y col., Proc. Natl. Acad. Sci. USA 88:9431 (1991); Chiamulera y col., Eur. J. Pharmacol. 216:335 (1992); Siliprandi y col., Eur. J. Pharmacol. 219:173 (1992); Pizzi y col., J. Neurochem. 61:683 (1993).Preliminary studies assessing therapeutic potentials with the available mGluR agonists and antagonists have apparently produced conflicting results. For example, it has been reported that the application of APCD on hypocampic neurons leads to strokes and neuronal damage (Sacaan et al., Neurosci. Lett. 139 : 77 (1992); Lipparti et al., Life Sci. 52 : 85 (1993) Other studies indicate, however, that ACPD inhibits epileptiform activity, and may also have neuroprotective properties Taschenberger et al., Neuroreport 3 : 629 (1992); Sheardown, Neuroreport 3 : 916 (1992); Koh et al., Proc. Natl. Acad. Sci. USA 88 : 9431 (1991); Chiamulera et al., Eur. J. Pharmacol. 216 : 335 (1992); Siliprandi et al., Eur. J. Pharmacol. 219 : 173 (1992); Pizzi et al., J. Neurochem. 61 : 683 (1993).

Es probable que estos resultados conflictivos se deban a la falta de selectividad de ACPD, la cual causa activación de varios subtipos diferentes de mGluR. En los estudios que encuentran daño neuronal aparece que los mGluR del Grupo I se activaron, por lo tanto potenciaron neurotransmisión excitadora indeseable. En los estudios que muestran efectos neuroprotectores aparece que tiene lugar la activación de los mGluR del Grupo II y/o del Grupo III, inhibiendo liberación de glutamato presináptica, y disminuyendo neurotransmisión excitadora.It is likely that these conflicting results are due to the lack of selectivity of ACPD, which causes activation of several different subtypes of mGluR. In the studies that find neuronal damage it appears that mGluR of Group I is activated, therefore enhanced excitatory neurotransmission undesirable. In studies showing neuroprotective effects it appears that the activation of Group II mGluRs and / or Group III, inhibiting release of presynaptic glutamate, and decreasing excitatory neurotransmission.

Esta interpretación es consistente con la observación de que (S)-4C3HPG, un antagonista de mGluR del Grupo I y agonista de mGluR del grupo II, protege contra ataques de apoplejía en ratones DBA/2, mientras los agonistas selectivos de mGluR del Grupo II DCG-IV y L-CCG-I protegen neuronas de toxicidad inducida por NMDA y KA. Thomsen y col., J. Neuchem. 62:2492 (1994); Bruno y col., Eur. J. Pharmacol. 256:109 (1994); Pizzi y col., J. Neurochem. 61:683 (1993).This interpretation is consistent with the observation that (S) -4C3HPG, a Group I mGluR antagonist and group II mGluR agonist, protects against strokes in DBA / 2 mice, while Group II mGluR selective agonists DCG-IV and L-CCG-I protect neurons from toxicity induced by NMDA and KA. Thomsen et al., J. Neuchem. 62 : 2492 (1994); Bruno et al., Eur. J. Pharmacol. 256 : 109 (1994); Pizzi et al., J. Neurochem. 61 : 683 (1993).

En base a lo precedente, está claro que los agonistas y antagonistas de mGluR tienen valor limitado, debido a su falta de potencia y selectividad. Además, la mayoría de los compuestos actualmente disponibles son aminoácidos o derivados de aminoácidos que tienen biodisponibilidades limitadas, obstaculizando de este modo estudios in vivo para valorar la fisiología mGluR, farmacología y su ponencial terapéutico. Los compuestos que inhiben selectivamente la activación de subtipo del receptor de Grupo I de glutamato metabotrópico serían útiles para el tratamiento de trastornos neurológicos y enfermedades tales como demencia senil, enfermedad de Parkinson, enfermedad de Alzheimer, Corea de Huntington, dolor, dolores de cabeza migrañosos, epilepsia, trauma en la cabeza, heridas isquémicas y anóxicas, trastornos psiquiátricos tales como esquizofrenia, depresión, y ansiedad, trastornos oftalmológicos tales como diversas retinopatías, por ejemplo, retinopatías diabéticas, glaucoma, y trastornos neurológicos de naturaleza auditiva tales como tinnitus, y trastornos de dolor neuropático, neuralgia postherpética y neuralgia trigeminal.Based on the foregoing, it is clear that mGluR agonists and antagonists have limited value, due to their lack of potency and selectivity. In addition, most of the currently available compounds are amino acids or amino acid derivatives that have limited bioavailability, thus impeding in vivo studies to assess mGluR physiology, pharmacology and their therapeutic potential. Compounds that selectively inhibit subtype activation of the Group I receptor of metabotropic glutamate would be useful for the treatment of neurological disorders and diseases such as senile dementia, Parkinson's disease, Alzheimer's disease, Huntington's Korea, pain, migraine headaches , epilepsy, head trauma, ischemic and anoxic wounds, psychiatric disorders such as schizophrenia, depression, and anxiety, ophthalmological disorders such as various retinopathies, for example, diabetic retinopathies, glaucoma, and neurological disorders of a hearing nature such as tinnitus, and Neuropathic pain disorders, postherpetic neuralgia and trigeminal neuralgia.

De acuerdo con ello, existe una necesidad de potentes agonistas y antagonistas de mGluR que manifiestan una elevada selectividad de un subtipo de mGluR, en particular un subtipo de receptor de Grupo 1.Accordingly, there is a need for potent mGluR agonists and antagonists that manifest a high selectivity of a subtype of mGluR, in particular a Group 1 receptor subtype.

Sumario de la invenciónSummary of the invention

Es un objeto de la presente invención, por lo tanto, identificar compuestos de receptor activo de glutamato metabotrópico los cuales presentan un alto grado de potencia y selectividad para subtipos de receptor de glutamato metabotrópico individual, y para proporcionar procedimientos de fabricar estos compuestos.It is an object of the present invention, therefore therefore, identify active glutamate receptor compounds metabotropic which have a high degree of power and selectivity for metabotropic glutamate receptor subtypes individual, and to provide manufacturing procedures for these compounds.

Es un objeto adicional de esta invención proporcionar composiciones farmacéuticas que contienen compuestos los cuales presentan un alto grado de potencia y selectividad de subtipos de receptor de glutamato metabotrópico individuales, y para proporcionar procedimientos de fabricar estas composiciones farmacéuticas.It is a further object of this invention provide pharmaceutical compositions containing compounds which have a high degree of power and selectivity of individual metabotropic glutamate receptor subtypes, and for provide methods of manufacturing these compositions Pharmaceuticals

Es aún otro objeto de esta invención proporcionar procedimientos de inhibir activación de un receptor mGluR de Grupo I, y de inhibir daño neuronal causado mediante activación excitadora de un receptor mGluR de Grupo I, específicamente mGluR5.It is yet another object of this invention to provide methods of inhibiting activation of a Group mGluR receptor I, and to inhibit neuronal damage caused by excitatory activation of a Group I mGluR receptor, specifically mGluR5.

Es aún otro objeto de esta invención proporcionar procedimientos de tratar una enfermedad asociada con activación excitadora de un receptor mGluR de Grupo I, específicamente mGluR5.It is yet another object of this invention to provide procedures of treating a disease associated with activation exciter of a Group I mGluR receptor, specifically mGluR5.

Para llevar a cabo estos y otros objetivos, la presente invención proporciona potentes antagonistas de mGluR de Grupo I, específicamente, mGluR5. Estos antagonistas se seleccionan deTo accomplish these and other objectives, the The present invention provides potent mGluR antagonists of Group I, specifically, mGluR5. These antagonists are selected from

a) un compuesto de fórmula II:a) a compound of formula II:

1one

en la quein the that

X e Y son N,X and Y are N,

Z es O;Z is O;

Ar^{1} es 2-piridilo y Ar^{2} es fenilo, en el que al menos uno de los restos Ar^{1} y Ar^{2} se sustituye con uno o más restos seleccionados del grupo que consta de -F, -Cl, -Br, -I, -SR, -SOR, -SO_{2}R, -SO_{2}NRR', -OCOR, -OCONRR', -NRCOR', -NRCO_{2}R', -CN, -CO_{2}R, -CONRR', -C(O)R, -CH(OR)R', -CH_{2}(OR), y -R;Ar1 is 2-pyridyl and Ar2 it is phenyl, wherein at least one of the residues Ar 1 and Ar 2 it is replaced with one or more remains selected from the group consisting of -F, -Cl, -Br, -I, -SR, -SOR, -SO 2 R, -SO 2 NRR ', -OCOR, -OCONRR ', -NRCOR', -NRCO_ {2} R ', -CN, -CO_ {2} R, -CONRR', -C (O) R, -CH (OR) R ', -CH_ {(}), and -R;

en el que R o R' se selecciona del grupo que consta de H, CF_{3}, alquilo(C_{1}-C_{10}), cicloalquilo, alquilarilo, heterocicloalquilo, arilo y donde R y R' pueden combinarse para formar un anillo,in which R or R 'is selected from the group that consists of H, CF 3, (C 1 -C 10) alkyl, cycloalkyl, alkylaryl, heterocycloalkyl, aryl and where R and R 'can combine to form a ring,

con la condición de que el compuesto no sea 3-(2-piridil)-5-(2-clorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-fenil-1,3,4-oxadiazol, o 3-(2-piridil)-5-[3-(trifluorometil)fenil]-1,24-oxadiazol; owith the proviso that the compound is not 3- (2-pyridyl) -5- (2-chlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5-phenyl-1,3,4-oxadiazole, or 3- (2-pyridyl) -5- [3- (trifluoromethyl) phenyl] -1,24-oxadiazole; or

b) 3-(2-piridil)-5-[3-(trifluorometoxi)fenil]-1,2,4-oxadiazol,b) 3- (2-pyridyl) -5- [3- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole,

3-(2-piridil)-5-(2,3-difluorofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (2,3-difluorophenyl) -1,2,4-oxadiazole,

3-(2-piridil)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole,

3-(5-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (5-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole,

3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol,3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole,

3-(2-piridil)-5-(3-nitrofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3-nitrophenyl) -1,2,4-oxadiazole,

2-[3-clorofenil]-4-[piridin-2-il]-1,3-oxazol,2- [3-chlorophenyl] -4- [pyridin-2-yl] -1,3-oxazole,

2-(3,5-diclorofenil)-4-[piridin-2-il]-1,3-oxazol,2- (3,5-dichlorophenyl) -4- [pyridin-2-yl] -1,3-oxazole,

2-(3-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(2-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (2-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-metilfenil)-4-(2-piridil)-1,3-oxazol,2- (3-methylphenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-trifluorometoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-Trifluoromethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(2,3-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(2,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3,5-dimetoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(2,3-diclorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-dichlorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-cloro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-fluoro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-fluoro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-cloro-5-fluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-fluorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-cianofenil)-4-(5-cloropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-chloropyrid-2-yl) -1,3-oxazole,

2-(3-cianofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole,

2-(3-ciano-5-fluorofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyano-5-fluorophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole,

2-(3-cianofenil)-4-(3-fluoropirid-3-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-fluoropyrid-3-yl) -1,3-oxazole,

2-(3,5-dimetoxifenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole,

2-(3-cianofenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole,

2-(3-cianofenil)-4-(3-cloro-5-trifluorometilpirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-chloro-5-trifluoromethylpyrid-2-yl) -1,3-oxazole,

2-(5-cloro-2-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Chloro-2-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(2-cloro-5-metiltiofenil)-4-(2-piridil)-1,3-oxazol,2- (2-Chloro-5-methylthiophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(5-bromo-5-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Bromo-5-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-clorofenil)-4-(piridin-2-il)-1,3-oxazol,2- (3-chlorophenyl) -4- (pyridin-2-yl) -1,3-oxazole,

2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-nitrofenil)-4-(2-piridil)-1,3-oxazol,2- (3-nitrophenyl) -4- (2-pyridyl) -1,3-oxazole,

2-(3-bromofenil)-4-(2-piridil)-1,3-oxazol, o2- (3-bromophenyl) -4- (2-pyridyl) -1,3-oxazole, or

una sal farmacéuticamente aceptable de los mismos.a pharmaceutically acceptable salt of same.

En una realización preferida de la invención, el compuesto se selecciona del grupo que consta de 3-(2-piridil)-5-(3,5-diclorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-clorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-metoxifenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2-clorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-(trifluorometil)fenil]-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-metilfenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(1-naftil)-1,2,4-oxadiazol, 3-(2-piridil)-5-[3-(trifluorometoxi)fenil]-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,3-difluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,5-difluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3,5-difluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3,5-diclorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,3-diclorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-cloro-cianofenil)-1,2-oxadiazol, 3-(2-piridil)-5-(3-fluoro-5-cianofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-cloro-5-fluorofenil)-1,2,4-oxadiazol, 3-(5-cloropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(5-fluroropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(5-fluroropirid-2-il)-5-(3-ciano-5-fluorofenil)-1,2,4-
oxadiazol, 3-(3-fluoropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(5-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol, 3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(2-quinolinil)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(3-cloro-5-trifluorometilpirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(5-cloro-2-metoxifenil)-1,2,4-
oxadiazol, 3-(2-piridil)-5-(2-cloro-5-metoxifenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2-bromo-5-metoxifenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,5,6-trifluorofenil)-1,2,4-oxadiazol, 2-[3-clorofenil]-4-[piridin-2-il]-1,3-oxazol y 3-(2-piridil)-5-(2,5,6-trifluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-nitrofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-bromofenil)-1,2,4-oxadiazol y sales farmacéuticamente aceptables de los mismos.In a preferred embodiment of the invention, the compound is selected from the group consisting of 3- (2-pyridyl) -5- (3,5-dichlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-methoxyphenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5 - (2-Chlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3- (trifluoromethyl) phenyl] -1,2,4-oxadiazole, 3- (2-pyridyl) - 5- (3-methylphenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (1-naphthyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- [3- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (2,3-difluorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (2,5-difluorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3,5-difluorophenyl) -1,2,4-oxadiazole, 3- (2- pyridyl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3- (2- pyridyl) -5- (3,5-dichlorophenyl) -1,2,4-oxadiazol, 3- (2-pyridyl) -5- (2,3-dichlorophenyl) -1,2,4-oxadiazole, 3- ( 2-pyridyl) -5- (3-chloro-cyanophenyl) -1,2-oxadiazole, 3- (2-pyridyl) -5- (3-fluoro-5-cyanophenyl) -1,2,4-oxadiazole, 3 - (2-pyridyl) -5- (3-c Parrot-5-fluorophenyl) -1,2,4-oxadiazole, 3- (5-chloropyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3- (5-fluroropyrid- 2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3- (5-fluroropyrid-2-yl) -5- (3-cyano-5-fluorophenyl) -1,2,4 -
oxadiazol, 3- (3-fluoropyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazol, 3- (5-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl ) -1,2,4-oxadiazol, 3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3- (2-quinolinyl) -5- (3 -cyanophenyl) -1,2,4-oxadiazole, 3- (3-chloro-5-trifluoromethylpyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl ) -5- (5-chloro-2-methoxyphenyl) -1,2,4-
oxadiazol, 3- (2-pyridyl) -5- (2-chloro-5-methoxyphenyl) -1,2,4-oxadiazol, 3- (2-pyridyl) -5- (2-bromo-5-methoxyphenyl) - 1,2,4-oxadiazole, 3- (2-pyridyl) -5- (2,5,6-trifluorophenyl) -1,2,4-oxadiazole, 2- [3-chlorophenyl] -4- [pyridin-2 -il] -1,3-oxazol and 3- (2-pyridyl) -5- (2,5,6-trifluorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3 -nitrophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-bromophenyl) -1,2,4-oxadiazole and pharmaceutically acceptable salts thereof.

De acuerdo con otra realización de la invención, se ha proporcionado una composición farmacéutica que comprende un compuesto como se expone anteriormente conjuntamente con un diluyente o excipiente farmacéuticamente aceptable.According to another embodiment of the invention, a pharmaceutical composition comprising a compound as set forth above in conjunction with a pharmaceutically acceptable diluent or excipient.

De acuerdo con aún otra realización de la invención, se ha proporcionado un procedimiento de fabricar un compuesto como se expone anteriormente. Específicamente, los compuestos de la invención se pueden preparar generalmente mediante formación del resto G entre dos compuestos precursores que contienen restos Ar^{1} y Ar^{2} adecuados. Cuando el ligando contiene un 1,2,4-oxadiazol, el heterociclo puede estar formado usando técnicas bien conocidas, tales como reacción entre una amidoxima y un cloruro ácido, o mediante la reacción de una aminozima y un acilimidazol. Una ilustración de una transformación tal se proporciona en los ejemplos del 3 a 6, más adelante.According to yet another embodiment of the invention, a method of manufacturing a compound as set forth above. Specifically, the Compounds of the invention can generally be prepared by formation of the G residue between two precursor compounds containing suitable Ar 1 and Ar 2 residues. When the ligand contains a 1,2,4-oxadiazole, the heterocycle may be formed using well known techniques, such as reaction between a amidoxime and an acid chloride, or by reacting a aminozyme and an acylimidazole. An illustration of a transformation such is provided in examples 3 to 6, below.

Las amidoximas se pueden preparar usando técnicas bien conocidas mediante la reacción de un nitrilo sustituido en Ar^{1} con hidroxilamina. Una ilustración de una transformación tal se proporciona más adelante en el ejemplo 1.The amidoximes can be prepared using techniques well known by reacting a substituted nitrile in Ar1 with hydroxylamine. An illustration of a transformation such is provided later in example 1.

En la mayoría de los casos, los cloruros de carbonilo del precursor de Ar^{2} están fácilmente disponibles, o se pueden preparar usando técnicas sencillas de química orgánica. Por ejemplo, los ácidos carboxílicos se pueden convertir en los correspondientes cloruros ácidos mediante reacción con, por ejemplo, cloruro de tionilo o cloruro de oxalilo.In most cases, chlorides of carbonyl of the Ar2 precursor are readily available, or They can be prepared using simple organic chemistry techniques. For example, carboxylic acids can be converted into corresponding acid chlorides by reaction with, for example, thionyl chloride or oxalyl chloride.

En el caso donde el ligando contiene un 1,3-oxazol, los compuestos se prepararon a partir del procedimiento similar a aquel dado por Kelly y col., J. Org. Chem. 61, 4623-4633 (1996). Se prepararon 1,3-oxazoles 3,5-disustituidos haciendo reaccionar una halocetona con carboxamida en someter a reflujo a tolueno durante 3 días. La mezcla resultante se dejó enfriar a temperatura ambiente, el disolvente se eliminó y el residuo se purificó.In the case where the ligand contains a 1,3-oxazole, the compounds were prepared from the procedure similar to that given by Kelly et al., J. Org. Chem. 61 , 4623-4633 (1996). 3,5-Disubstituted 1,3-oxazoles were prepared by reacting a haloketone with carboxamide in refluxing toluene for 3 days. The resulting mixture was allowed to cool to room temperature, the solvent was removed and the residue was purified.

De acuerdo con una realización adicional de la invención, se ha proporcionado un uso de los compuestos definido anteriormente para la preparación de un medicamento para el tratamiento de enfermedades o trastornos asociados con receptores metabotrópicos de glutamato.According to a further embodiment of the invention, a defined use of the compounds has been provided previously for the preparation of a medicine for the treatment of diseases or disorders associated with receptors metabotropic glutamate.

La enfermedad o trastorno se selecciona preferiblemente del grupo que consta de demencia senil, enfermedad de Parkinson, enfermedad de Alzheimer, Corea de Huntington, dolor, dolores de cabeza migrañosos, epilepsia, trauma en la cabeza, heridas isquémicas y anóxicas, trastornos psiquiátricos tales como esquizofrenia, depresión, ansiedad, neuropatías diabéticas, neuropatías inducidas por quimioterapia, neuralgia postherpética, y neuralgia trigeminal.The disease or disorder is selected preferably from the group consisting of senile dementia, disease of Parkinson's, Alzheimer's disease, Huntington's Korea, pain, migraine headaches, epilepsy, head trauma, ischemic and anoxic wounds, psychiatric disorders such as schizophrenia, depression, anxiety, diabetic neuropathies, chemotherapy-induced neuropathies, postherpetic neuralgia, and trigeminal neuralgia.

Otros objetos, características y ventajas de la presente invención llegarán a ser evidentes a partir de la siguiente descripción detallada.Other objects, features and advantages of the present invention will become apparent from the following detailed description.

Breve descripción de los dibujosBrief description of the drawings

La figura 1 muestra compuestos ilustrativos de esta invención.Figure 1 shows illustrative compounds of this invention.

Descripción detallada de la invenciónDetailed description of the invention

La presente invención proporciona compuestos como se definen anteriormente que son antagonistas potentes y selectivos de mGluR5.The present invention provides compounds such as defined above that are potent and selective antagonists of mGluR5.

Preparación de antagonistas de mGluR del Grupo IPreparation of Group I mGluR antagonists

Muchos materiales de partida para preparar los compuestos de la presente invención están disponibles a partir de fuentes comerciales, tales como Aldrich Chemical Company (Milwaukee, WI). Además, los compuestos de la invención se preparan fácilmente, a partir de precursores disponibles, usando transformaciones sencillas las cuales se conocen bien en la técnica. El artesano experto reconocerá que los antagonistas del Grupo I mGluR, de acuerdo con la invención, se pueden preparar por medio de metodología que se conoce bien, usando técnicas ampliamente reconocidas de química orgánica. Las reacciones adecuadas se describen en libros de texto estándar de química orgánica. Por ejemplo, véase March, ADVANCED ORGANIC CHEMISTRY, 2ª ed., McGraw Hill (1977).Many starting materials for preparing the compounds of the present invention are available from commercial sources, such as Aldrich Chemical Company (Milwaukee, WI). In addition, the compounds of the invention are readily prepared, from available precursors, using simple transformations which are well known in the art. The skilled artisan will recognize that Group I mGluR antagonists, according to the invention, can be prepared by means of a well-known methodology, using widely recognized organic chemistry techniques. Suitable reactions are described in standard textbooks of organic chemistry. For example, see March, ADVANCED ORGANIC CHEMISTRY , 2nd ed., McGraw Hill (1977).

Más específicamente, los compuestos de la invención se pueden preparar generalmente mediante formación del resto G entre dos compuestos precursores que contienen motivos Ar^{1} y Ar^{2} adecuados. Cuando el ligando contiene un 1,2,4-oxadiazol, el heterociclo se puede formar usando técnicas bien conocidas, tales como reacción entre una amidoxima y un cloruro ácido, o mediante la reacción entre una amidoxima y un aclimidazol. Una ilustración de tal transformación se proporciona en ejemplos del 3 al 6, más adelante.More specifically, the compounds of the invention can generally be prepared by forming the G residue between two precursor compounds containing motifs Ar 1 and Ar 2 suitable. When the ligand contains a 1,2,4-oxadiazole, the heterocycle can be formed using well known techniques, such as reaction between a amidoxime and an acid chloride, or by the reaction between a Amidoxime and an aclimidazole. An illustration of such a transformation is provide in examples 3 to 6, later.

Las amidoximas se pueden preparar usando técnicas bien conocidas mediante la reacción de un nitrilo sustituido en Ar^{1} con hidroxilamina. Una ilustración de una transformación tal se proporciona más adelante en el ejemplo
1.The amidoximes can be prepared using well known techniques by reacting a nitrile substituted on Ar1 with hydroxylamine. An illustration of such a transformation is provided later in the example.
one.

En la mayoría de los casos, los cloruros ácidos del precursor Ar^{2} están fácilmente disponibles, o se pueden preparar usando técnicas sencillas de química orgánica. Por ejemplo, los ácidos carboxílicos se pueden convertir en los cloruros ácidos correspondientes mediante reacción con, por ejemplo, cloruro de tionilo o cloruro de oxalilo.In most cases, acid chlorides of the precursor Ar2 are readily available, or can be Prepare using simple organic chemistry techniques. For example, carboxylic acids can be converted into acid chlorides corresponding by reaction with, for example, thionyl or oxalyl chloride.

En el caso en que el ligando contenga un 1,3-oxazol, los compuestos se prepararon usando un procedimiento similar al que se da por Kelly y col., J. Org. Chem. 61, 4623-4633 (1996). Así, los 1,3-oxazoles 3,5-disustituidos se prepararon mezclando una halocetona con carboxamida en tolueno a reflujo durante 3 días. La mezcla resultante se dejó enfriar a temperatura ambiente, el disolvente se eliminó y el residuo se purificó.In the case where the ligand contains a 1,3-oxazole, the compounds were prepared using a procedure similar to that given by Kelly et al., J. Org. Chem. 61 , 4623-4633 (1996). Thus, 3,5-disubstituted 1,3-oxazoles were prepared by mixing a haloketone with carboxamide in toluene at reflux for 3 days. The resulting mixture was allowed to cool to room temperature, the solvent was removed and the residue was purified.

Puesta a prueba de los compuestos para la actividad antagonista de los mGluR de Grupo ITesting of compounds for antagonistic activity of Group I mGluR

Las propiedades farmacológicas de los compuestos de la invención se pueden analizar usando análisis estándar para actividad funcional. Ejemplos de ensayos del receptor de glutamato se conocen bien en la técnica, por ejemplo, véase Aramori y col., Neuron 8:757 (1992); Tanabe y col., Neuron 8:169 (1992); Miller y col., J. Neuroscience 15: 6103 (1995); Balazs, y col., Neurochemistry 69:151 (1997).The pharmacological properties of the compounds of the invention can be analyzed using standard analysis for functional activity. Examples of glutamate receptor assays are well known in the art, for example, see Aramori et al., Neuron 8: 757 (1992); Tanabe et al., Neuron 8: 169 (1992); Miller et al., J. Neuroscience 15: 6103 (1995); Balazs, et al., Neurochemistry 69: 151 (1997).

Convenientemente, los compuestos de la invención se pueden estudiar por medio de un ensayo que mide la movilización del calcio intracelular [Ca^{2+}]_{i} en células que expresan mGluR5 que pueden unir los compuestos. Una línea celular bien conocida la cual es adecuada para este propósito se describe por Miller y col. J. Neuroscience 15: 6103 (1995), los contenidos de la cual se incorporan por la presente mediante referencia. Se muestra que la exposición de los astrocitos de rata a los factores de crecimiento factor de crecimiento de fibroblastos básico, EGF, o factor-á de crecimiento transformante incrementan marcadamente la expresión de proteínas y la actividad funcional de mGluR5 endógena (Miller y col., J. Neuroscience, 15(9): 6103-6109, 1995).Conveniently, the compounds of the invention can be studied by means of an assay that measures the mobilization of intracellular calcium [Ca 2+] i in cells expressing mGluR5 that can bind the compounds. A well known cell line which is suitable for this purpose is described by Miller et al. J. Neuroscience 15: 6103 (1995), the contents of which are hereby incorporated by reference. It is shown that exposure of rat astrocytes to growth factors of basic fibroblast growth factor, EGF, or transforming growth factor-a markedly increases protein expression and functional activity of endogenous mGluR5 (Miller et al., J. Neuroscience, 15 (9) : 6103-6109, 1995).

En breve, se prepararon cultivos de astrocitos primarios de 3-5 días de edad de cachorros de ratas Sprage-Dawley usando una modificación de Miller y col., y se plaquearon en matraces recubiertos en medio Eagle modificado de Dulbecco (DMEM) que contiene suero de ternera fetal (FCS). Para análisis de cubeta, los cultivos se regularon al alza con factores de crecimiento en matraces durante 3-5 días, después se recogieron y prepararon para medida de movilización de [Ca^{2+}]_{i} como se describe previamente (Nemeth y col., 1998):Soon, astrocyte cultures were prepared 3-5 day old puppies of rats Sprage-Dawley using a Miller modification and col., and were plated in eagle-coated flasks modified Dulbecco (DMEM) containing fetal calf serum (FCS). For cuvette analysis, the crops were regulated upwards with growth factors in flasks for 3-5 days, then they were collected and prepared for mobilization measure of [Ca 2 +] i as previously described (Nemeth and col., 1998):

Para análisis de lector de placa de imagen fluorescente (FLIPR), las células se sembraron en placas de 96 pocillos de fondo claro recubiertas de lisina poli-D con lados negros y el análisis de movilización de [Ca^{2+}]_{i} se llevó a cabo tres días tras la regulación al alza del factor de crecimiento.For image plate reader analysis fluorescent (FLIPR), cells were seeded in 96 plates clear bottom wells coated with poly-D lysine with black sides and the mobilization analysis of [Ca 2 +] i was carried out three days after upward regulation of growth factor.

Los experimentos de PLIPR se llevaron a cabo usando un ajuste de láser de 0,800 W y una velocidad de obturador de cámara CCD de 0,4 segundos. Cada experimento FLIPR se inició con 180 \mul de tampón presente en cada pocillo de la placa celular. Después de cada adición de compuesto, la señal de fluorescencia se probó 50 veces a intervalos de 1 segundo seguidos por 3 muestras a intervalos de 5 segundos. Las respuestas midieron en la altura de pico de la respuesta dentro del periodo de muestreo.PLIPR experiments were carried out using a laser setting of 0.800 W and a shutter speed of 0.4 second CCD camera. Each FLIPR experiment started with 180 µl of buffer present in each well of the cell plate. After each compound addition, the fluorescence signal is tested 50 times at 1 second intervals followed by 3 samples at 5 second intervals. Responses measured at the height of peak response within the sampling period.

Cada determinación de CE_{50} y CI_{50} se realizó de datos obtenidos a partir de curvas de respuesta a concentración (CRC) de 8 puntos realizadas por duplicado. Las CRC de agonista se generaron ajustando todas las respuestas a escala de la máxima respuesta observada para la placa. El bloque antagonista de la prueba del agonista se normalizó a la respuesta media de la prueba de agonista en 14 pocillos controles en la misma placa. Un protocolo detallado para probar los compuestos de la invención se proporciona más adelante en el ejemplo 4.Each determination of CE 50 and IC 50 is performed data obtained from response curves to concentration (CRC) of 8 points made in duplicate. The CRC of agonist were generated by adjusting all responses to scale of the maximum response observed for the plate. The antagonist block of the agonist test was normalized to the average response of the agonist test in 14 control wells on the same plate. A Detailed protocol to test the compounds of the invention is provided later in example 4.

Preparación de la composición farmacéutica que contiene antagonistas mGluR, y su uso en tratar trastornos neurológicosPreparation of the pharmaceutical composition it contains mGluR antagonists, and their use in treating neurological disorders

Los compuestos de la presente invención son útiles para tratar trastornos o enfermedades neurológicos. Mientras estos compuestos se usarán típicamente en terapia para pacientes humanos, se pueden usar también en medicina veterinaria, para tratar enfermedades similares o idénticas.The compounds of the present invention are Useful for treating neurological disorders or diseases. While these compounds will typically be used in patient therapy humans, can also be used in veterinary medicine, to treat similar or identical diseases.

En aplicaciones terapéuticas y/o diagnósticas, los compuestos de la invención se pueden formular por una diversidad de procedimientos de administración, incluyendo administración sistémica y tópica o localizada. Las técnicas y formulaciones generalmente se pueden encontrar en REMINGTON'S PHARMACEUTICAL SCIENCES (18ª ed.), Mack Publishing Co (1990).In therapeutic and / or diagnostic applications, the compounds of the invention can be formulated by a variety of administration procedures, including systemic and topical or localized administration. Techniques and formulations can generally be found in REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed.), Mack Publishing Co (1990).

Los compuestos de acuerdo con la invención son efectivos durante un amplio intervalo de dosificaciones. Por ejemplo, en el tratamiento de humanos adultos, se pueden usar dosificaciones de aproximadamente 0,01 a aproximadamente 1000 mg por 60-70 kg de adulto, preferiblemente de aproximadamente 0,5 a aproximadamente 100 mg por 60-70 kg de adulto, por [día] dosis. La dosificación exacta dependerá de la vía de administración, la forma en que la cual se administra el compuesto, el sujeto a tratarse, el peso corporal del sujeto a tratarse, y la preferencia y experiencia del médico que atiende.The compounds according to the invention are effective over a wide range of dosages. By example, in the treatment of adult humans, they can be used dosages of about 0.01 to about 1000 mg per 60-70 kg adult, preferably about 0.5 to about 100 mg per 60-70 kg of adult, per [day] dose. Dosage exact will depend on the route of administration, the way in which the which compound is administered, the subject to be treated, the weight body of the subject to be treated, and the preference and experience of attending doctor

Las sales farmacéuticamente aceptables se conocen bien generalmente por aquellos de habilidad normal en la técnica, y pueden incluir, por medio de ejemplo pero sin limitación, acetato, bencenosulfonato, besilato, benzoato, bicarbonato, bitartrato, bromuro, edetato de calcio, camsilato, carbonato, citrato, edetato, edisilato, estolato, esilato, fumarato, gluceptato, gluconato, glutamato, glicolilarsanilato, hexilresorcinato, hidrabamina, bromhidrato, clorhidrato, hidronaftoato, yoduro, isetionato, lactato, lactobionato, malato, maleato, mandelato, mesilato, mucato, napsilato, nitrato, pamoato (embonato), pantotenato, fosfato/difosfato, poligalacturanato, salicilato, estearato, subacetato, succinato, sulfato, tanato, tartrato, o teoclato. Se pueden encontrar otras sales farmacéuticamente aceptables, por ejemplo, en REMINGTON'S PHARMACEUTICAL SCIENCES (18 ª ed.), supra.Pharmaceutically acceptable salts are generally well known to those of ordinary skill in the art, and may include, by way of example but not limited to, acetate, benzenesulfonate, besylate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate , citrate, edetate, edisilate, estolate, esilate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanlate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydronaphthate, iodide, isethionate, lactate, lactobionate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate, malate , nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturanato, salicylate, stearate, subacetate, succinate, sulfate, tanate, tartrate, or theoclate. Other pharmaceutically acceptable salts can be found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed.), Supra .

Las sales farmacéuticamente aceptales preferidas incluyen, por ejemplo, acetato, benzoato, bromuro, carbonato, citrato, gluconato, bromhidrato, clorhidrato, matato, mesilato, napsilato, pamoato (embonato), fosfato, salicilato, succinato, sulfato o tartrato.Preferred pharmaceutically acceptable salts include, for example, acetate, benzoate, bromide, carbonate, citrate, gluconate, hydrobromide, hydrochloride, matate, mesylate, napsilate, pamoate (embonate), phosphate, salicylate, succinate, sulfate or tartrate.

Dependiendo de las condiciones específicas que se tratan, tales agentes se pueden formular en dosificaciones líquidas o sólidas y administrarse sistemáticamente o localmente. Los agentes se pueden administrar, por ejemplo, en una forma programada o continuada como se sabe por aquellos expertos en la técnica. Las técnicas para formulación y administración se pueden encontrar en REMINGTON'S PHARMACEUTICAL SCIENCES (18ª ed.), supra. Las vías adecuadas pueden incluir administración oral, bucal, sublingual, rectal, trasdérmica, vaginal, mucosal, nasal o intestinal; administración parenteral, incluyendo inyecciones intramusculares, subcutáneas, intramedulares, igual que inyecciones intratecales, intraventriculares directas, intravenosas, intraperitoneales, intranasales, o intraoculares, entre otras.Depending on the specific conditions being treated, such agents can be formulated in liquid or solid dosages and administered systematically or locally. Agents can be administered, for example, in a scheduled or continuous manner as is known to those skilled in the art. Techniques for formulation and administration can be found in REMINGTON'S PHARMACEUTICAL SCIENCES (18th ed.), Supra . Suitable routes may include oral, oral, sublingual, rectal, transdermal, vaginal, mucosal, nasal or intestinal administration; parenteral administration, including intramuscular, subcutaneous, intramedullary injections, as well as direct intrathecal, intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, among others.

Para inyección, los agentes de la invención se pueden formular en disoluciones acuosas, preferiblemente en tampones fisiológicamente compatible tales como disolución de Hank, disolución de Ringer, o tampón salino fisiológico. Para administración transmucosal, los penetrantes apropiados para que la barrera se haga permeable se usan en la formulación. Tales penetrantes generalmente se conocen en la técnica.For injection, the agents of the invention are they can formulate in aqueous solutions, preferably in buffers physiologically compatible such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, the appropriate penetrants so that the barrier becomes permeable are used in the formulation. Such Penetrants are generally known in the art.

El uso de los vehículos farmacéuticamente aceptables para formular los compuestos descritos en el presente documento para la práctica de la invención en dosificaciones adecuadas para administración sistémica está dentro del alcance de la invención. Con elección apropiada del vehículo y adecuada práctica de elaboración, las composiciones de la presente invención, en particular, aquellas formuladas como disoluciones, se pueden administrar parenteralmente, tal como mediante inyección intravenosa. Los compuestos se pueden formular adecuadamente usando vehículos farmacéuticamente aceptables bien conocidos en la técnica en dosificaciones adecuadas para administración oral. Tales vehículos permiten a los compuestos de la invención formularse como comprimidos, píldoras, cápsulas, líquidos, geles, jarabes, lodos, suspensiones y similares, para ingestión oral por un paciente a ser tratado.The use of pharmaceutical vehicles acceptable to formulate the compounds described herein document for the practice of the invention in dosages suitable for systemic administration is within the scope of the invention. With appropriate vehicle choice and adequate manufacturing practice, the compositions of the present invention, in particular, those formulated as solutions, can be administer parenterally, such as by injection intravenous Compounds can be adequately formulated using Pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such vehicles allow the compounds of the invention to be formulated as tablets, pills, capsules, liquids, gels, syrups, sludges, suspensions and the like, for oral ingestion by a patient to be treaty.

Las composiciones farmacéuticas adecuadas para usar en la presente invención incluyen composiciones en las que los ingredientes activos están contenidos en una cantidad efectiva para lograr su propósito deseado. La determinación de las cantidades efectivas está bien dentro de la capacidad de aquellos expertos en la técnica, especialmente a la luz de la discusión detallada proporcionada en el presente documento.Pharmaceutical compositions suitable for used in the present invention include compositions in which the active ingredients are contained in an effective amount to Achieve your desired purpose. The determination of the quantities effective is well within the capacity of those experts in the technique, especially in light of the detailed discussion provided in this document.

Además de los ingredientes activos, estas composiciones farmacéuticas pueden contener vehículos aceptables farmacéuticamente adecuados que comprenden excipientes y auxiliares los cuales facilitan el procesamiento de los compuestos activos en preparaciones las cuales pueden usarse farmacéuticamente. Las preparaciones formuladas para administración oral pueden estar en forma de comprimidos, grageas, cápsulas, o disoluciones.In addition to the active ingredients, you are pharmaceutical compositions may contain acceptable vehicles pharmaceutically suitable comprising excipients and auxiliaries which facilitate the processing of active compounds in preparations which can be used pharmaceutically. The Preparations formulated for oral administration may be in form of tablets, dragees, capsules, or solutions.

Las preparaciones farmacéuticas para uso oral se pueden obtener combinando los compuestos activos con excipientes sólidos, opcionalmente moliendo una mezcla resultante, y procesando la mezcla de gránulos, después de añadir auxiliares adecuados, si se desea, para obtener comprimidos o núcleos de grageas. Los excipientes adecuados son, en particular, filtros tales como azúcares, incluyendo lactosa, sacarosa, manitol, o sorbitol; preparaciones de celulosa, por ejemplo, almidón de maíz, almidón de trigo, almidón de arroz, almidón de patata, gelatina, goma de tragacanto, metilcelulosa, hidroxipropilmetilcelulosa, carboximetil celulosa de sodio (CMC), y/o polivinilpirrolidona (PVP: povidona). Si se desea, se pueden añadir agentes disgregantes, tales como la polivinilpirrolidona entrecruzada, agar, o ácido algínico o una sal del mismo tal como alginato de sodio.Pharmaceutical preparations for oral use are can be obtained by combining the active compounds with excipients solids, optionally grinding a resulting mixture, and processing the granule mixture, after adding suitable auxiliaries, if you want, to get tablets or dragee cores. The Suitable excipients are, in particular, filters such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, for example, corn starch, starch wheat, rice starch, potato starch, jelly, gum tragacanth, methylcellulose, hydroxypropylmethylcellulose, carboxymethyl sodium cellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Los núcleos de grageas se proporcionan con recubrimientos adecuados. Para este propósito se pueden usar disoluciones concentradas de azúcar , las cuales pueden obtener opcionalmente goma arábiga, talco, polivinilpirrolidona, gel de carbopol, polietilenglicol (PEG), y/o dióxido de titanio, disoluciones de laca, y disolventes orgánicos adecuados o mezclas de disolventes. Se pueden añadir productos de tinción o pigmentos a los comprimidos o recubrimientos de grageas para identificación o para caracterizar diferentes combinaciones de dosis de compuestos activos.Dragee cores are provided with suitable coatings. For this purpose they can be used concentrated sugar solutions, which you can get optionally gum arabic, talc, polyvinylpyrrolidone, gel carbopol, polyethylene glycol (PEG), and / or titanium dioxide, lacquer solutions, and suitable organic solvents or mixtures of solvents Staining products or pigments can be added to tablets or dragee coatings for identification or for characterize different dose combinations of compounds assets.

Las preparaciones farmacéuticas las cuales se pueden usar oralmente incluyen cápsulas ajustadas a presión hechas de gelatina, igual que cápsulas blandas, selladas, hechas de gelatina, y un plastificador, tal como glicerol y sorbitol. Las cápsulas ajustadas a presión hechas de gelatina pueden contener los ingredientes activos en mezcla con agente de carga tal como lactosa, agentes aglutinantes tales como almidones, y/o lubricantes tales como talco o estearato de magnesio y, opcionalmente, estabilizadores. En las cápsulas blandas, los compuestos activos se pueden disolver o suspender en líquidos adecuados, tales como aceites grasos, parafina líquida, o polietilenglicoles (PEG) líquidos. Además, se pueden añadir estabilizadores.Pharmaceutical preparations which are can use orally include pressure-adjusted capsules made of gelatin, same as soft, sealed capsules, made of gelatin, and a plasticizer, such as glycerol and sorbitol. The Pressure-adjusted capsules made of gelatin may contain the active ingredients in admixture with filler such as lactose, binding agents such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers In soft capsules, the active compounds are they can dissolve or suspend in suitable liquids, such as fatty oils, liquid paraffin, or polyethylene glycols (PEG) liquids In addition, stabilizers can be added.

La presente invención, generalmente así descrita, se entenderá más fácilmente mediante referencia a los siguientes ejemplos, los cuales se proporcionan a modo de ilustración y no se desean para ser limitantes de la presente invención.The present invention, generally thus described, it will be more easily understood by reference to the following examples, which are provided by way of illustration and not they wish to be limiting of the present invention.

Ejemplos Examples Procedimientos Experimentales GeneralesGeneral Experimental Procedures

Los datos de cromatografía de gases capilar y de espectro de masas se obtuvieron usando un Cromatografo de Gases de la Serie II 5890 de Hewlett-Packard (HP) acoplado a un Detector Selectivo de Masas de la serie 5971 [Columna Capilar de Realización Ultra-2 Ultra (silicona PhMe entrecruzada al 5%); longitud de la columna, 25 m; diámetro interno de la columna 0,20 mm; velocidad de flujo del helio, 60 ml/min.; inyector temporal. 250ºC; programa de temperaturas, 20ºC/minuto de 125 a 325ºC durante 10 minutos, después se mantuvo constante a 325ºC durante 6 minutos]. La cromatografía en capa fina se llevó a cabo usando placas de TLC HF de gel de sílice de 250 \muM Uniplaca Analtech: luz UV algunas veces en conjunción con ninhidrina y reactivos de punverización de Dragendorff (Sigma Chemical Co.) se usaron para detectar compuestos en las placas TLC. La mayoría de los reactivos usados en reacciones se llevaron a cabo a partir del Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (San Luís, MO), Fluka Chemical Corp. (Milwaukee, WI), Fisher Scientific (Pittsburgh, PA), TCI America (Portland, OR), o Lancaster Synthesis (Windham, NH);Capillary gas chromatography data and Mass spectrum was obtained using a Gas Chromatograph of Hewlett-Packard (HP) Series II 5890 coupled to a 5971 Series Selective Mass Detector [Capillary Column of Ultra-2 Ultra realization (PhMe silicone crosslinked to 5%); column length, 25 m; internal diameter 0.20 mm column; helium flow rate, 60 ml / min .; temporary injector 250 ° C; temperature program, 20ºC / minute of 125 at 325 ° C for 10 minutes, then kept constant at 325 ° C for 6 minutes]. Thin layer chromatography was carried out. using 250 µM Uniplaca silica gel HF TLC plates Analtech: UV light sometimes in conjunction with ninhydrin and puncture reagents from Dragendorff (Sigma Chemical Co.) se used to detect compounds in TLC plates. Most of the reagents used in reactions were carried out from the Aldrich Chemical Co. (Milwaukee, WI), Sigma Chemical Co. (St. Louis, MO), Fluka Chemical Corp. (Milwaukee, WI), Fisher Scientific (Pittsburgh, PA), TCI America (Portland, OR), or Lancaster Synthesis (Windham, NH);

Ejemplo 1Example 1 Síntesis de intermediarios de amidoxinaSynthesis of amidoxin intermediates

Pirid-2-ilaminaPyrid-2-ylamine

22

Usando el procedimiento de Shine y col., J. Heterocyclic Chem. (1989) 26:125-128, se trató clorhidrato de hidroxilamina (7,65 g, 110 mmol) en etanol (100 ml) con una disolución de hidróxido de sodio (11 ml de 10 N, 110 mmol). Un precipitado formado rápidamente y la mezcla de reacción se agitó a temperatura ambiente durante 30 minutos. El precipitado inorgánico se filtró y aclaró con etanol (100 ml). El filtrado y los lavados con etanol se combinaron y trataron con 2-cianopiridina (10,4 g, 100 mmol). La mezcla de reacción se calentó a reflujo durante 20 horas. Los volátiles se eliminaron a vacío proporcionando 13,3 g (97%) de pirid-2-iladoxima.Using the procedure of Shine et al., J. Heterocyclic Chem . (1989) 26 : 125-128, hydroxylamine hydrochloride (7.65 g, 110 mmol) in ethanol (100 ml) was treated with a solution of sodium hydroxide (11 ml of 10 N , 110 mmol). A rapidly formed precipitate and the reaction mixture was stirred at room temperature for 30 minutes. The inorganic precipitate was filtered and rinsed with ethanol (100 ml). The filtrate and the washings with ethanol were combined and treated with 2-cyanopyridine (10.4 g, 100 mmol). The reaction mixture was heated at reflux for 20 hours. Volatiles were removed in vacuo to provide 13.3 g (97%) of pyrid-2-ylaxime.

5-cloropirid-2-ilaminoxima5-chloropyrid-2-ylaminoxime

33

Una mezcla de 2,5-diciclopiridina (1,48 g, 10 mmol), cianuro de cinc (705 mg, 6 mmol), cinc (polvo, 29 mg, 0,45 mmol), [1,1'-bis(difenilfosfino)ferroceno]dicloropaladio(II), en complejo con diclorometano (1:1) (0,18 g, 0,22 mmol) en N,N-dimetilformamida (10 ml) se calentó a reflujo durante 5 horas. Después de enfriar, la reacción se diluyó con acetato de etilo y se extrajo con agua y salmuera. La cromatografía en gel de sílice proporcionó 753 mg (53%) de 2-ciano-5-cloropiridina.A mixture of 2,5-dicyclopyridine (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol), zinc (powder, 29 mg, 0.45 mmol), [1,1'-bis ( diphenylphosphino) ferrocene] dichloropaladium (II), in complex with dichloromethane (1: 1) (0.18 g, 0.22 mmol) in N, N- dimethylformamide (10 ml) was heated at reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography provided 753 mg (53%) of 2-cyano-5-chloropyridine.

Usando el procedimiento general para la síntesis de amidoximas, 2-ciano-5-cloropiridina (753 mg, 5,3 mmol), una disolución de clorhidrato de hidroxilamina (1,2 ml de 5 M, 6 mmol) en etanol (7 ml), e hidróxido de sodio (0,61 ml de 10 N, 6,1 mmol), se calentaron a reflujo durante 24 horas. Un estímulo estándar proporcionó 707 mg (77%) de 5-cloropirid-2-ilamidoxima.Using the general procedure for the synthesis of amidoximes, 2-cyano-5-chloropyridine (753 mg, 5.3 mmol), a solution of hydroxylamine hydrochloride (1.2 ml of 5 M, 6 mmol) in ethanol (7 ml ), and sodium hydroxide (0.61 ml of 10 N , 6.1 mmol), were refluxed for 24 hours. A standard stimulus provided 707 mg (77%) of 5-chloropyrid-2-ylamidoxime.

5-fluoropirid-2-ilamidoxima5-fluoropyrid-2-ylamidoxime

44 

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Una mezcla de 2-ciano-5-cloropiridina (1 g, 7,22 mmol) y fluoruro de potasio (1,26 g, 21,68 mmol) en 1-metil-2-pirrolidinona (25 ml) se calentaron a reflujo 18 horas. Después de enfriar, la reacción se diluyó con acetato de etilo y se extrajo con agua y salmuera. Los disolventes orgánicos se eliminaron después al vacío. La cromatografía en gel de sílice del residuo proporcionó 425 mg (48%) de 2-ciano-5-fluoropiridina.A mix of 2-cyano-5-chloropyridine (1 g, 7.22 mmol) and potassium fluoride (1.26 g, 21.68 mmol) in 1-methyl-2-pyrrolidinone (25 ml) were heated at reflux 18 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. The organic solvents were then removed in vacuo. Silica gel chromatography of the residue provided 425 mg. (48%) of 2-cyano-5-fluoropyridine.

Usando el procedimiento general para la síntesis de amidoximas, se calentaron a reflujo durante 24 horas 2-ciano-5-fluoropiridina (425 mg, 3,48 mmol), una disolución de clorhidrato de hidroxilamina (0,79 ml de 5 M, 3,95 mmol) en etanol (5 ml), e hidruro de sodio (0,398 ml de 10 N, 3,98 mmol). Un estímulo estándar proporcionó 330 mg (61%) de 5-fluoropirid-2-ilamidoxima.Using the general procedure for the synthesis of amidoximes, 2-cyano-5-fluoropyridine (425 mg, 3.48 mmol), a solution of hydroxylamine hydrochloride (0.79 ml of 5 M, 3) were heated at reflux for 24 hours. , 95 mmol) in ethanol (5 ml), and sodium hydride (0.368 ml of 10 N , 3.98 mmol). A standard stimulus provided 330 mg (61%) of 5-fluoropyrid-2-ylamidoxime.

5-metoxipirid-2-ilamidoxima5-methoxypyrid-2-ylamidoxime

55 

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Una disolución de 2-ciano-5-fluoropiridina (0,65 g, 5,3 mmol) en metóxido de sodio (disolución de 1,83 ml al 25% en peso en metanol, 7,95 mmol) se agitó a 0ºC durante 1,5 horas y 2 horas a temperatura ambiente. La reacción se diluyó después con acetato de etilo y se extrajo con agua y salmuera. La eliminación del disolvente a vacío proporcionó 304 mg (43%) de 2-ciano-5-metoxipiridina.A solution of 2-cyano-5-fluoropyridine (0.65 g, 5.3 mmol) in sodium methoxide (1.83 ml solution at 25% by weight in methanol, 7.95 mmol) was stirred at 0 ° C for 1.5 hours and 2 hours at room temperature. The reaction was then diluted with ethyl acetate and extracted with water and brine. The elimination of the solvent in vacuo provided 304 mg (43%) of 2-cyano-5-methoxypyridine.

Usando el procedimiento general para la síntesis de amidoximas, se calentaron a reflujo durante 24 horas 2-ciano-5-metoxipiridina (270 mg, 2,01 mmol), una disolución de clorhidrato de hidroxilamina (0,457 ml de 5 M, 2,28 mmol) en etanol (4 ml), e hidróxido de sodio (0,230 ml de 10 N; 2,30 mmol). Un estímulo estándar proporcionó 79 mg (24%) de 5-metoxipirid-2-ilamidoxima.Using the general procedure for the synthesis of amidoximes, 2-cyano-5-methoxypyridine (270 mg, 2.01 mmol), a solution of hydroxylamine hydrochloride (0.457 ml of 5 M, 2.28) were refluxed for 24 hours mmol) in ethanol (4 ml), and sodium hydroxide (0.230 ml of 10 N ; 2.30 mmol). A standard stimulus provided 79 mg (24%) of 5-methoxypyrid-2-ylamidoxime.

3-fluoropirid-2-ilamidoxima3-fluoropyrid-2-ylamidoxime

66 

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Una mezcla de 2,3-dicloropiridina (1,48 g, 10 mmol), cianuro de cinc (705 mg, 6 mmol), cinc (polvo, 29 mg, 0,45 mmol), [1,1'-bis(difenilfosfino)ferroceno]dicloropaladio(II), en complejo con diclorometano (1:1) (0,18 g, 0,22 mol) en N,N-dimetilformamida (10 ml) se calentó a reflujo durante 5 horas. Después de enfriar, la reacción se diluyó con acetato de etilo y se extrajo con agua y salmuera. La eliminación del disolvente y la cromatografía en gel de sílice proporcionaron 1,05 g (76%) de 2-ciano-3-cloropiridina.A mixture of 2,3-dichloropyridine (1.48 g, 10 mmol), zinc cyanide (705 mg, 6 mmol), zinc (powder, 29 mg, 0.45 mmol), [1,1'-bis ( diphenylphosphino) ferrocene] dichloropaladium (II), in complex with dichloromethane (1: 1) (0.18 g, 0.22 mol) in N, N- dimethylformamide (10 ml) was heated at reflux for 5 hours. After cooling, the reaction was diluted with ethyl acetate and extracted with water and brine. Solvent removal and silica gel chromatography provided 1.05 g (76%) of 2-cyano-3-chloropyridine.

Una disolución de 2-ciano-3-cloropiridina (1 g, 7,22 mmol) en 1-metil-2-pirrolidinona (25 ml) se trató con fluoruro de potasio (1,26 g, 21,68 mmol) y se calentó a reflujo durante 18 horas. Después de enfriar, la reacción se diluyó con acetato de etilo y se extrajo con agua y salmuera. La cromatografía en gel de sílice proporcionó 442 mg (50%) de 2-ciano-3-fluoropiridina.A solution of 2-cyano-3-chloropyridine (1 g, 7.22 mmol) in 1-methyl-2-pyrrolidinone (25 ml) was treated with potassium fluoride (1.26 g, 21.68 mmol) and was heated to reflux for 18 hours. After cooling, the reaction It was diluted with ethyl acetate and extracted with water and brine. The silica gel chromatography provided 442 mg (50%) of 2-cyano-3-fluoropyridine.

Usando el procedimiento general para la síntesis de amidoximas, 2-ciano-3-fluoropiridina (442 mg, 3,62 mmol), una disolución de clorhidrato de hidroxilamina (0,82 ml de 5 M, 4,1 mmol) en etanol (5 ml), e hidruro de sodio (0,415 ml de 10 N, 4,15 mmol) se calentó a reflujo durante 24 horas. Un estímulo estándar proporcionó 368 mg (66%) de 3-fluoropirid-3-ilamidoxima.Using the general procedure for the synthesis of amidoximes, 2-cyano-3-fluoropyridine (442 mg, 3.62 mmol), a solution of hydroxylamine hydrochloride (0.82 ml of 5 M, 4.1 mmol) in ethanol ( 5 ml), and sodium hydride (0.415 ml of 10 N , 4.15 mmol) was heated at reflux for 24 hours. A standard stimulus provided 368 mg (66%) of 3-fluoropyrid-3-ylamidoxime.

Quinol-2-ilamidoximaQuinol-2-ylamidoxime

77 

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Usando el procedimiento general para la síntesis de amidoximas, 2-quinolinacarbonitrilo (1,02 g, 6,6 mmol), una disolución de clorhidrato de hidroxilamina (1,44 ml de disolución 5 N, 7,2 mmol) en etanol (10 ml), e hidruro de sodio (0,72 ml de disolución 10 N, 7,2 mmol) se calentó a reflujo durante 18 horas. Un estímulo estándar proporcionó 990 mg (80%) de quinol-2-ilaminodoxima.Using the general procedure for the synthesis of amidoximes, 2-quinolinecarbonitrile (1.02 g, 6.6 mmol), a solution of hydroxylamine hydrochloride (1.44 ml of 5 N solution, 7.2 mmol) in ethanol (10 ml), and sodium hydride (0.72 ml of 10 N solution, 7.2 mmol) was heated at reflux for 18 hours. A standard stimulus provided 990 mg (80%) of quinol-2-ylaminodoxime.

Ejemplo 2Example 2 Síntesis de intermediarios del ácido carboxílicoSynthesis of carboxylic acid intermediates

Ácido 3-cloro-5-cianobenzoicoAcid 3-chloro-5-cyanobenzoic

88 

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Una mezcla de 3,5-diclorobenzoato de metilo (14,66 g, 71,5 mmol), cianuro de cinc (5,04 g, 42,9 mmol), cinc (polvo, 0,21 g, 3,21 mmol), [1,1'bis(difenilfosfino)ferroceno]dicloropaladio(II), en complejo con diclorometano (1:1) (1,3 g, 1,57 mmol) en N,N-dimetilformamida (70 ml) se calentó a reflujo durante 5 horas. Después de enfriarse la reacción se diluyó con acetato de etilo y se extrajo con agua y salmuera. La cromatografía en gel de sílice proporcionó 2,34 g (17%) de 2-cloro-5-cianobenzoato de metilo.A mixture of methyl 3,5-dichlorobenzoate (14.66 g, 71.5 mmol), zinc cyanide (5.04 g, 42.9 mmol), zinc (powder, 0.21 g, 3.21 mmol ), [1,1'bis (diphenylphosphino) ferrocene] dichloropaladium (II), in complex with dichloromethane (1: 1) (1.3 g, 1.57 mmol) in N, N- dimethylformamide (70 ml) was heated at reflux for 5 hours. After cooling the reaction was diluted with ethyl acetate and extracted with water and brine. Silica gel chromatography provided 2.34 g (17%) of methyl 2-chloro-5-cyanobenzoate.

El éster intermedio se trató con una disolución de hidróxido de sodio (7,5 ml de disolución 4 N, 30 mmol) en metanol (50 ml) y se agitó a temperatura ambiente durante 18 horas. El disolvente se eliminó al vacío y el residuo se disolvió en acetato de etilo. La disolución orgánica se lavó con HCl al 5% y salmuera. La eliminación del disolvente proporcionó 1,8 g (83%) de ácido 3-cloro-5-cianobenzoico.The intermediate ester was treated with a solution of sodium hydroxide (7.5 ml of 4 N solution, 30 mmol) in methanol (50 ml) and stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with 5% HCl and brine. Solvent removal provided 1.8 g (83%) of 3-chloro-5-cyanobenzoic acid.

Ácido 3-cloro-5-fluorobenzoicoAcid 3-chloro-5-fluorobenzoic

99

Una mezcla de 1-bromo-3-cloro-5-fluorobenceno (25,0 g, 120 mmol), cianuro de cinc (8,45 g, 72 mmol) cinc (polvo, 235 mg, 3,6 mmol), [1,1'Bis(difenilfosfino)ferroceno]dicloropaladio(II), en complejo con diclorometano (1:1) (1,5 g, 1,8 mmol) en N,N-dimetilformamida (70 ml) se calentó a reflujo durante 1 hora. Después de este tiempo la disolución se enfrió y se acidificó con ácido clorhídrico concentrado. La extracción con diclorometano y evaporación del disolvente proporcionó 15,14 g (85%) de ácido 3-cloro-5-fluorobenzoico.A mixture of 1-bromo-3-chloro-5-fluorobenzene (25.0 g, 120 mmol), zinc cyanide (8.45 g, 72 mmol) zinc (powder, 235 mg, 3.6 mmol), [ 1,1'Bis (diphenylphosphino) ferrocene] dichloropaladium (II), in complex with dichloromethane (1: 1) (1.5 g, 1.8 mmol) in N, N- dimethylformamide (70 ml) was heated at reflux for 1 hour. After this time the solution was cooled and acidified with concentrated hydrochloric acid. Extraction with dichloromethane and solvent evaporation provided 15.14 g (85%) of 3-chloro-5-fluorobenzoic acid.

Ácido 3-fluoro-5-cianobenzoicoAcid 3-fluoro-5-cyanobenzoic

1010

El ácido 3-cloro-5-fluorobenzoico (13,74 g, 78,7 mmol) se trató con 50 ml de cloruro de tionilo y se calentó a reflujo durante 2 horas. El exceso de cloruro de tionilo se eliminó al vacío y el residuo se trató con 100 ml de metanol seco para producir 13,6 (92%) de 3-cloro-5-fluorobenzoato de metilo.Acid 3-chloro-5-fluorobenzoic (13.74 g, 78.7 mmol) was treated with 50 ml of thionyl chloride and heated to reflux for 2 hours. Excess thionyl chloride it was removed in vacuo and the residue was treated with 100 ml of dry methanol to produce 13.6 (92%) of 3-chloro-5-fluorobenzoate of methyl

Una mezcla de 3-cloro-5-fluorobenzoato de metilo, cianuro de cinc (8,46 g, 72,3 mmol), cinc (polvo, 235 mg, 3,6 mmol) [1,1'Bis(difenilfosfino)ferroceno]dicloropaladio(II), en complejo con diclorometano (1:1) (1,5 g, 1,8 mmol) en N,N-dimetilformamida (70 ml) se calentó a reflujo durante 2 horas. La disolución se calentó a temperatura ambiente y se diluyó con acetato de etilo. La disolución orgánica se extrajo con agua y salmuera y se concentró a vacío, proporcionando 3-cloro-5-cianobenzoato de metilo en bruto.A mixture of methyl 3-chloro-5-fluorobenzoate, zinc cyanide (8.46 g, 72.3 mmol), zinc (powder, 235 mg, 3.6 mmol) [1,1'Bis (diphenylphosphino) ferrocene ] dichloropaladium (II), in complex with dichloromethane (1: 1) (1.5 g, 1.8 mmol) in N, N- dimethylformamide (70 ml) was heated at reflux for 2 hours. The solution was heated to room temperature and diluted with ethyl acetate. The organic solution was extracted with water and brine and concentrated in vacuo to afford crude methyl 3-chloro-5-cyanobenzoate.

El 3-cloro-5-cianobenzoato de metilo en bruto se tratño con una disolucón de hidróxido de sodio (45 ml de disolución 4 N, 180 mmol) en metanol (350 ml) a temperatura ambiente durante 4 horas. El disolvente se eliminó a vacío y el residuo se disolvió en acetato de etilo. La disolución orgánica se lavó con HCl acuoso al 5% y salmuera. La cromatografía en gel de sílice proporcionó 7,0 g (54%) de ácido 3-fluoro-5-cianobenzoicoThe crude methyl 3-chloro-5-cyanobenzoate was treated with a solution of sodium hydroxide (45 ml of 4 N solution, 180 mmol) in methanol (350 ml) at room temperature for 4 hours. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with 5% aqueous HCl and brine. Silica gel chromatography provided 7.0 g (54%) of 3-fluoro-5-cyanobenzoic acid

Ejemplo 3Example 3 Síntesis de 1,2,4-oxadiazoles 3,5-disustituidos de cloruros ácidosSynthesis of 1,2,4-oxadiazoles 3,5-disubstituted acid chlorides

En general, se hicieron modificaciones de los procedimientos dados por Shine y col., J. Heterocyclic Chem. (1989) 26:125-128. Se fabricaron 1,2,4-oxadiazoles 3,5-disustituidos añadiendo un cloruro de acilo a una disolución de una amidoxima en piridina después de lo cual la mezcla de reacción bien se calentó a reflujo o bien se situó en un tubo sellado y se calentó. Típicamente, los oxadiazoles se aislaron precipitando con agua fría y filtrando o mediante extracción con un disolvente orgánico. Si es necesario, los oxadiazoles se purificaron mediante cromatografía o recristalización.In general, modifications were made to the procedures given by Shine et al., J. Heterocyclic Chem . (1989) 26: 125-128. 1,2,4-3,5-disubstituted 1,2,4-oxadiazoles were manufactured by adding an acyl chloride to a solution of an amidoxime in pyridine after which the reaction mixture was either heated to reflux or placed in a sealed tube and It warmed up. Typically, oxadiazoles were isolated by precipitating with cold water and filtering or by extraction with an organic solvent. If necessary, the oxadiazoles were purified by chromatography or recrystallization.

3-(2-piridil)-5-(3,5-diclorofenil)-1,2,4-oxadiazol (NPS 64982) (404) B23- (2-pyridyl) -5- (3,5-dichlorophenyl) -1,2,4-oxadiazole (NPS 64982) (404) B2

11eleven

Una mezcla de cloruro de 3,5-diclorobenzoílo (2,1 g, 10 mmol) y pirid-2-ilaminodoxima (1,37 g, 10 mmol) en piridina (5 ml) se calentó en tubo sellado a 190ºC durante 2 horas. Después de este tiempo, la mezcla de reacción se añadió mediante filtración, se lavó con agua y después se neutralizó a partir de etanol para producir 2,1 g (72%) de 3-(2-piridil)-5-(3,5-diclorofenil)-1,2,4-oxadiazol: p.f.: 162-166ºC; CG/EI-EM proporcionó m/z (rel. int.) 291 257 (M^{+}, 38), 293 (25), 261 (1), 145 (113), 120 (100), 90 (20), 78 (28), 51 (15).A mixture of 3,5-dichlorobenzoyl chloride (2.1 g, 10 mmol) and pyrid-2-ylaminodoxime (1.37 g, 10 mmol) in pyridine (5 ml) was heated in a sealed tube at 190 ° C for 2 hours . After this time, the reaction mixture was added by filtration, washed with water and then neutralized from ethanol to yield 2.1 g (72%) of 3- (2-pyridyl) -5- (3, 5-dichlorophenyl) -1,2,4-oxadiazole: mp: 162-166 ° C; CG / EI-MS provided m / z (rel. Int.) 291 257 (M +, 38), 293 (25), 261 (1), 145 (113), 120 (100), 90 (20 ), 78 (28), 51 (15).

3-(2-piridil)-5-(3-clorofenil)-1,2,4-oxadiazol/NPS 64983) (405) B33- (2-pyridyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole / NPS 64983) (405) B3

1212

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3-clorobenzoílo (127 \mul, 1 mmol) y pirid-2-ilaminoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a reflujo durante 4 horas. Un estímulo estándar proporcionó 156 mg (61%) de 3-3-(piridil)-5-(3-clorofenil)-1,2,4-oxadiazol: m.p.: 136-140ºC; GC/IE-EM proporcionó m/z (rel. int.) 257 (M^{+}, 64), 259 (21), 227 (3), 120 (100), 111 (22), 90 (24), 78 (32), 75 (26), 51 (20).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-chlorobenzoyl chloride (127 µL, 1 mmol) and pyrid-2-ylaminoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated at reflux for 4 hours. A standard stimulus provided 156 mg (61%) of 3-3- (pyridyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole: mp: 136-140 ° C; GC / IE-EM provided m / z (int. Rel.) 257 (M +, 64), 259 (21), 227 (3), 120 (100), 111 (22), 90 (24) , 78 (32), 75 (26), 51 (20).

3-(2-piridil)-5-(3-metoxifenil)-1,2,4-oxadiazol B13- (2-pyridyl) -5- (3-methoxyphenyl) -1,2,4-oxadiazole B1

1313

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3-anisoílo (151 \mul, 1 mmol) y pirid-2-ilaminoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a reflujo durante 4 horas. Un estímulo estándar proporcionó 200 mg (79%) de 3-(2-piridil)-5-(3-metoxifenil)-1,2,4-oxadiazol: m.p. 96-99ºC; GC/IE-EM proporcionó m/z (rel. int.) 253 (M^{+}, 100), 223 (3), 179 (3), 135 (74), 133 (90), 92 (27), 78 (29), 77 (32), 64 (23), 63 (23).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-anisoyl chloride (151 µL, 1 mmol) and pyrid-2-ylaminoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated at reflux for 4 hours. A standard stimulus provided 200 mg (79%) of 3- (2-pyridyl) -5- (3-methoxyphenyl) -1,2,4-oxadiazole: mp 96-99 ° C; GC / IE-EM provided m / z (rel. Int.) 253 (M +, 100), 223 (3), 179 (3), 135 (74), 133 (90), 92 (27) , 78 (29), 77 (32), 64 (23), 63 (23). 

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3-(2-piridil)-5-(2-clorofenil)-1,2,4-oxadiazol (B5)3- (2-pyridyl) -5- (2-chlorophenyl) -1,2,4-oxadiazole (B5)

1414

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 2-clorobenzoílo (127 \mul, 1 mmol) y pirid-2-ilaminoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a reflujo durante 4 horas. Un estímulo estándar proporcionó 157 mg (61%) de 3-(2-piridil)-5-(2-clorofenil)-1,2,4-oxadiazol: m.p. 93-94ºC; GC/IE-EM proporcionó m/z (rel. int.) 257 (M^{+}, 76), 259 (26), 227 (4), 139 (11), 120 (100), 111 (21), 90 (27) 78 (35), 75 (29), 51 (21)Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2-chlorobenzoyl chloride (127 µL, 1 mmol) and pyrid-2-ylaminoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated at reflux for 4 hours. A standard stimulus provided 157 mg (61%) of 3- (2-pyridyl) -5- (2-chlorophenyl) -1,2,4-oxadiazole: mp 93-94 ° C; GC / IE-EM provided m / z (int. Rel.) 257 (M +, 76), 259 (26), 227 (4), 139 (11), 120 (100), 111 (21) , 90 (27) 78 (35), 75 (29), 51 (21)

3-(2-piridil)-5-[3-(trifluorometil)fenil]-1,2,4-oxadiazol (B6)3- (2-pyridyl) -5- [3- (trifluoromethyl) phenyl] -1,2,4-oxadiazole (B6)

15fifteen

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles,, cloruro de 3-(trifluorometil)benzoílo (151 \mul, 1 mmol) y pirid-2-ilaminoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a reflujo durante 16 horas. Un estímulo estándar proporcionó 233 mg (80%) de 3-(2-piridil)-5-[3-(trifluorometil)fenil]-1,2,4-oxadiazol: p.f.: 116-118ºC; GC/IE-EM proporcionó m/z (rel. int.) 291 (M^{+}, 81), 272 (7), 173 (6), 145 (25), 120 (100), 90 (20), 78 (23), 51 (11).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3- (trifluoromethyl) benzoyl chloride (151 µL, 1 mmol) and pyrid-2-ylaminoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated at reflux for 16 hours. A standard stimulus provided 233 mg (80%) of 3- (2-pyridyl) -5- [3- (trifluoromethyl) phenyl] -1,2,4-oxadiazole: mp: 116-118 ° C; GC / IE-MS provided m / z (rel. Int.) 291 (M +, 81), 272 (7), 173 (6), 145 (25), 120 (100), 90 (20) , 78 (23), 51 (11).

3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol (B7)3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole (B7)

1616

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3-fluorobenzoílo (122 \mul, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a reflujo durante 16 horas. Un estímulo estándar proporcionó 176 mg (73%) de 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.: 88-98ºC, GC/IE-EM proporcionó m/z (rel. int.) 241 (M^{+}, 95), 211 (5), 120 (100), 107 (13), 95 (30), 90 (21), 78 (27), 75 (19), 51 (15).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-fluorobenzoyl chloride (122 µL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated at reflux for 16 hours. A standard stimulus provided 176 mg (73%) of 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 88-98 ° C, GC / IE-MS provided m / z (rel. int.) 241 (M +, 95), 211 (5), 120 (100), 107 (13), 95 (30), 90 (21), 78 (27), 75 (19 ), 51 (15).

3-(2-piridil)-5-(3-metilfenil)-1,2,4-oxadiazol (B9)3- (2-pyridyl) -5- (3-methylphenyl) -1,2,4-oxadiazole (B9)

1717

Usando el procedimiento general de la síntesis de 1,2,4-oxadiazoles, cloruro de 3-touloílo (264 \mul, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en tubo sellado a 200ºC durante 2 horas. Un estímulo estándar proporcionó 387 mg (82%) de 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.:127-128ºC; GC/IE-EM proporcionó m/z (rel. int.) 237 (M^{+}, 100), 222 (2), 207 (8), 120 (68), 117 (24), 91 (29), 90 (29), 78 (32), 65 (26), 51 (23).Using the general procedure of the synthesis of 1,2,4-oxadiazoles, 3-touloyl chloride (264 µL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated in a sealed tube at 200 ° C for 2 hours. A standard stimulus provided 387 mg (82%) of 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 127-128 ° C; GC / IE-EM provided m / z (int. Rel.) 237 (M +, 100), 222 (2), 207 (8), 120 (68), 117 (24), 91 (29) , 90 (29), 78 (32), 65 (26), 51 (23).

3-(2-piridil)-5-(1-naftil)-1,2,4-oxadiazol (B10)3- (2-pyridyl) -5- (1-naphthyl) -1,2,4-oxadiazole (B10)

1818 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 1-naftoílo (150 \mul, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en tubo sellado a 200ºC durante 3 horas. Un estímulo estándar proporcionó 50 mg (18%) de 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.:132-136ºC; GC/IE-EM proporcionó m/z (rel. int.) 273 (M^{+}, 75), 195 (5), 169 (88), 153 (100), 139 (12), 127 (66), 126 (29), 105 (23), 78 (14), 51 (14).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 1-naphthoyl chloride (150 µL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated in sealed tube at 200 ° C for 3 hours. A standard stimulus provided 50 mg (18%) of 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 132-136 ° C; GC / IE-EM provided m / z (rel. Int.) 273 (M +, 75), 195 (5), 169 (88), 153 (100), 139 (12), 127 (66) , 126 (29), 105 (23), 78 (14), 51 (14).

3-(2-piridil)-5-[3-(trifluorometoxi)fenil]-1,2,4-oxadiazol (B11)3- (2-pyridyl) -5- [3- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole (B11)

1919 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3-(trifluorometoxi)benzoílo (220 mg, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentó en un tubo sellado a 200ºC durante 3 horas. Un estímulo estándar proporcionó 175 mg (57%) de 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.: 86-88ºC; GC/IE-EM proporcionó m/z (rel. int.) 307 (M^{+}, 73), 277 (3), 222 (3), 189 (6), 161 (5), 120 (100), 78 (21), 69 (17), 51 (10).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3- (trifluoromethoxy) benzoyl chloride (220 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) It was heated in a sealed tube at 200 ° C for 3 hours. A standard stimulus provided 175 mg (57%) of 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 86-88 ° C; GC / IE-EM provided m / z (rel. Int.) 307 (M +, 73), 277 (3), 222 (3), 189 (6), 161 (5), 120 (100) , 78 (21), 69 (17), 51 (10).

3-(2-piridil)-5-(2,3-diflurorofenil)-1,2,4-oxadiazol (B16)3- (2-pyridyl) -5- (2,3-diflurorophenyl) -1,2,4-oxadiazole (B16)

20twenty 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 2,3-difluorobenzoílo (124 \mul, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 100ºC durante 16 horas. Un estímulo estándar proporcionó 158 mg (61%) de 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.: 120-121ºC; GC/IE-EM proporcionó m/z (rel. int.) 259 (M^{+}, 97), 229 (5), 228 (4), 141 (11), 120 (100), 113 (26), 90 (27), 78 (34), 51 (17).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,3-difluorobenzoyl chloride (124 µL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) They were heated at 100 ° C for 16 hours. A standard stimulus provided 158 mg (61%) of 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 120-121 ° C; GC / IE-EM provided m / z (int. Rel.) 259 (M +, 97), 229 (5), 228 (4), 141 (11), 120 (100), 113 (26) , 90 (27), 78 (34), 51 (17).

3-(2-piridil)-5-(2,5-diflurorofenil)-1,2,4-oxadiazol (B17)3- (2-pyridyl) -5- (2,5-diflurorophenyl) -1,2,4-oxadiazole (B17)

21twenty-one 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 2,5-difluorobenzoílo (124 \mul, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 100ºC durante 16 horas. Un estímulo estándar proporcionó 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.: 120-126ºC; GC/IE-EM proporcionó m/z (rel. int.) 259 (M^{+}, 97), 229 (5), 228 (4), 141 (13), 120 (100), 113 (25), 90 (23), 78 (27), 51 (14).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,5-difluorobenzoyl chloride (124 µL, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) They were heated at 100 ° C for 16 hours. A standard stimulus provided 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 120-126 ° C; GC / IE-EM provided m / z (int. Rel.) 259 (M +, 97), 229 (5), 228 (4), 141 (13), 120 (100), 113 (25) , 90 (23), 78 (27), 51 (14).

3-(2-piridil)-5-(3,5-diflurorofenil)-1,2,4-oxadiazol (B18)3- (2-pyridyl) -5- (3,5-diflurorophenyl) -1,2,4-oxadiazole (B18)

2222 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3,5-difluorobenzoílo (1,25 ml, 10 mmol) y pirid-2-ilamidoxima (137 g, 10 mmol) en piridina (5 ml) se calentaron en un tubo sellado a 2001C durante 4 horas. Un estímulo estándar proporcionó 1,2 g (46%) de 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.: 115-119ºC; GC/IE-EM proporcionó m/z (rel. int.) 259 (M^{+}, 97), 229 (4), 228 (5), 141 (9), 125 (13), 113 (30), 90 (19), 78 (27), 63 (23), 51 (15).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-difluorobenzoyl chloride (1.25 ml, 10 mmol) and pyrid-2-ylamidoxime (137 g, 10 mmol) in pyridine (5 ml ) were heated in a sealed tube at 2001C for 4 hours. A standard stimulus provided 1.2 g (46%) of 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 115-119 ° C; GC / IE-MS provided m / z (rel. Int.) 259 (M +, 97), 229 (4), 228 (5), 141 (9), 125 (13), 113 (30) , 90 (19), 78 (27), 63 (23), 51 (15).

3-(2-piridil)-5-(3-cianofenil)-1,2,4-oxadiazol (B21)3- (2-pyridyl) -5- (3-cyanophenyl) -1,2,4-oxadiazole (B21)

232. 3

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3-cianobenzoílo (165 mg, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 100ºC durante 72 horas. Un estímulo estándar proporcionó 158 mg (64%) de 3-(2-piridil)-5-(3-fluorofenil)-1,2,4-oxadiazol: p.f.: 148-149ºC; GC/IE-EM proporcionó m/z (rel. int.) 248 (M^{+}, 859, 218 (5), 130 (6), 120 (100), 114 (9), 102 (28), 90 (26), 78 (37), 75 (19), 51 (30).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (165 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated to 100 ° C for 72 hours. A standard stimulus provided 158 mg (64%) of 3- (2-pyridyl) -5- (3-fluorophenyl) -1,2,4-oxadiazole: mp: 148-149 ° C; GC / IE-EM provided m / z (rel. Int.) 248 (M +, 859, 218 (5), 130 (6), 120 (100), 114 (9), 102 (28), 90 (26), 78 (37), 75 (19), 51 (30).

3-(2-piridil)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol (B23)3- (2-pyridyl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole (B23)

2424

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3,5-dimetoxibenzoílo (200 mg, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 100ºC durante 72 horas. Un estímulo estándar proporcionó 210 mg (74%) de 3-(2-piridil)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol: p.f.: 145-148ºC; GC/IE-EM proporcionó m/z (rel. int.) 283 (M^{+}, 100), 253 (3), 165 (69), 163 (19), 137 (36), 122 (33), 107 (17), 90 (10), 78 (25), 63 (19), 51 (19).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-dimethoxybenzoyl chloride (200 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) heated at 100 ° C for 72 hours. A standard stimulus provided 210 mg (74%) of 3- (2-pyridyl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole: mp: 145-148 ° C; GC / IE-MS provided m / z (rel. Int.) 283 (M +, 100), 253 (3), 165 (69), 163 (19), 137 (36), 122 (33) , 107 (17), 90 (10), 78 (25), 63 (19), 51 (19).

3-(2-piridil)-5-(2,3-diclorofenil)-1,2,4-oxadiazol (B25)3- (2-pyridyl) -5- (2,3-dichlorophenyl) -1,2,4-oxadiazole (B25)

2525

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 2,3-diclorobenzoílo (209 mg, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 100ºC durante 48 horas. Un estímulo estándar proporcionó 236 mg (81%) de 3-(2-piridil)-5-(2,3-diclorofenil)-1,2,4.-oxadiazol: p.f.: 128-133ºC; GC/IE-EM proporcionó m/z (rel. int.) 291 (M^{+}, 669, 293 (43), 256 (6), 173 (10), 145 (11), 120 (100), 90 (19), 78 (27), 51 (14).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 2,3-dichlorobenzoyl chloride (209 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) heated at 100 ° C for 48 hours. A standard stimulus provided 236 mg (81%) of 3- (2-pyridyl) -5- (2,3-dichlorophenyl) -1,2,4.-oxadiazole: mp: 128-133 ° C; GC / IE-EM provided m / z (rel. Int.) 291 (M +, 669, 293 (43), 256 (6), 173 (10), 145 (11), 120 (100), 90 (19), 78 (27), 51 (14).

3-(2-piridil)-5-(3-cloro-5-cianofenil)-1,2,4-oxadiazol (B26)3- (2-pyridyl) -5- (3-chloro-5-cyanophenyl) -1,2,4-oxadiazole (B26)

2626

El ácido 3-cloro-5-cianobenzoico (0,82 g, 4,97 mmol) se trató con una disolución de cloruro de oxalilo (10 ml de 2,5 M en diclorometano) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante 2,5 horas. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 3-cloro-5-cianobenzoílo.3-Chloro-5-cyanobenzoic acid (0.82 g, 4.97 mmol) was treated with a solution of oxalyl chloride (10 ml of 2.5 M in dichloromethane) and a catalytic amount of N, N- dimethylformamide . The reaction was stirred at room temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to provide 3-chloro-5-cyanobenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-cloro-5-cianobenzoílo y pirid-2-ilamidoxima (682 mg, 5 mmol, 1 equivalente) en piridina (5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar proporcionó 250 mg (19%) de 3-(2-piridil)-5-(3-cloro-5-cianofenil)-1,2,4-oxadiazol: GC/IE-EM proporcionó m/z (rel. int.) 282 (M^{+}, 100), 283 (18), 284 (34), 251 (4), 136 (10), 120 (53), 100 (10), 78 (15), 51 (6).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-chloro-5-cyanobenzoyl chloride and pyrid-2-ylamidoxime (682 mg, 5 mmol, 1 equivalent) in pyridine (5 ml) were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus provided 250 mg (19%) of 3- (2-pyridyl) -5- (3-chloro-5-cyanophenyl) -1,2,4-oxadiazole: GC / IE-MS provided m / z (rel . int.) 282 (M +, 100), 283 (18), 284 (34), 251 (4), 136 (10), 120 (53), 100 (10), 78 (15), 51 (6). 

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3-(2-piridil)-5-(3-fluoro-5-cianofenil)-1,2,4-oxadiazol (B27)3- (2-pyridyl) -5- (3-fluoro-5-cyanophenyl) -1,2,4-oxadiazole (B27)

2727

El ácido 3-fluoro-5-cianobenzoico (2,5 g, 15,14 mmol) se trató con una disolución de cloruro de oxalilo (30 ml 2,5 M en diclorometano, 75 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante 2,5 horas. El exceso de cloruro de oxalilo se eliminó al vacío proporcionando cloruro de 3-fluoro-5-cianobenzoílo.3-Fluoro-5-cyanobenzoic acid (2.5 g, 15.14 mmol) was treated with a solution of oxalyl chloride (30 ml 2.5 M in dichloromethane, 75 mmol) and a catalytic amount of N, N -dimethylformamide. The reaction was stirred at room temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to provide 3-fluoro-5-cyanobenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-fluoro-5-cianobenzoílo y pirid-2-ilamodotoxima (2,076 g, 15,25 mmol, 1 equivalente) en piridina (5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar y la recristalización a partir de 2-propanol proporcionaron 1,5 g (37%) de 3-(2-piridil)-5-(3-fluoro-5-cianofenil)-1,2,4-oxadiazol: GC/IE-EM proporcionó m/z (rel. int.) 266 (M^{+}, 81), 267 (13), 235 (5), 132 (12), 120 (100), 100 (18), 90 (18), 78 (35), 51 (20).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-fluoro-5-cyanobenzoyl chloride and pyrid-2-ylamodotoxime (2,076 g, 15.25 mmol, 1 equivalent) in pyridine (5 ml) They were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus and recrystallization from 2-propanol provided 1.5 g (37%) of 3- (2-pyridyl) -5- (3-fluoro-5-cyanophenyl) -1,2,4-oxadiazole: GC / IE-EM provided m / z (rel. Int.) 266 (M +, 81), 267 (13), 235 (5), 132 (12), 120 (100), 100 (18) , 90 (18), 78 (35), 51 (20).

3-(2-piridil)-5-(3-cloro-5-cianofenil)-1,2,4-oxadiazol (B28)3- (2-pyridyl) -5- (3-chloro-5-cyanophenyl) -1,2,4-oxadiazole (B28)

2828

El ácido 3-cloro-5-fluorobenzoico (400 mg, 2,3 mmol) se trató con una disolución de cloruro de oxalilo (4,6 ml de 2,5 M en diclorometano, 11,5 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante 2,5 horas. El cloruro de oxalilo en exceso se eliminó al vacío proporcionando cloruro 3-cloro-5-fluorobenzoílo.3-Chloro-5-fluorobenzoic acid (400 mg, 2.3 mmol) was treated with a solution of oxalyl chloride (4.6 ml of 2.5 M in dichloromethane, 11.5 mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to provide 3-chloro-5-fluorobenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-cloro-5-fluorobenzoílo y pirid-2-ilamidoxima (314 mg, 2,3 mmol, 1 equivalente) en piridina (5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar y la recristalización a partir de 2-propanol proporcionaron 250 mg (30%) de 3-(2-piridil)-5-(3-cloro-5-fluorofenil)-1,2,4-oxadiazol: GC/IE-EM proporcionó m/z (rel. int.) 275 (M^{+}, 89), 276 (14), 277 (29), 129 (26), 120 (100=, 109 (7), 90 (20), 78 (31), 51 (14).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-chloro-5-fluorobenzoyl chloride and pyrid-2-ylamidoxime (314 mg, 2.3 mmol, 1 equivalent) in pyridine (5 ml) They were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus and recrystallization from 2-propanol provided 250 mg (30%) of 3- (2-pyridyl) -5- (3-chloro-5-fluorophenyl) -1,2,4-oxadiazole: GC / IE-MS provided m / z (int. Rel.) 275 (M +, 89), 276 (14), 277 (29), 129 (26), 120 (100 =, 109 (7), 90 (20), 78 (31), 51 (14).

3-(5-cloropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadioazol (B29)3- (5-chloropyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadioazole (B29)

2929 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-cianobenzoílo (675 mg, 4 mmol) y 5-cloropirid-2-ilamidoxima (686 mg, 4 mmol) en piridina (5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar y la recristalización a partir de 2-propanol proporcionaron 357 mg (32%) de 3-(5-cloropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol: GC/IE-EM proporcionó m/z (rel. int.) 282 (M^{+}, 85), 283 (14), 284 (27), 156 (31), 154 (100), 112 (19), 102 (30=, 76 (28), 64 (13).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (675 mg, 4 mmol) and 5-chloropyrid-2-ylamidoxime (686 mg, 4 mmol) in pyridine (5 ml) They were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus and recrystallization from 2-propanol provided 357 mg (32%) of 3- (5-chloropyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole: GC / IE-MS provided m / z (int. Rel.) 282 (M +, 85), 283 (14), 284 (27), 156 (31), 154 (100), 112 (19), 102 (30 =, 76 (28), 64 (13).

3-(5-fluoropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadioazol (B30)3- (5-fluoropyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadioazole (B30)

3030 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-cianobenzoílo (0,534 g, 3,2 mmol) y 5-fluoropirid-2-ilamidoxima (0,5 g, 3,2 mmol) en piridina (5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar y la recristalización a partir de 2-propanol proporcionaron 370 mg (43%) de 3-(5-fluoropirid.2.il)-5-(3-cianofenil)-1,2,4-oxadiazol: GC/EI-MS proporcionó m/z (rel. int.) 266 (M^{+}, 100), 267 (10), 138 (80), 114 (8), 102 (19), 96 (22), 76 (17), 57 (8).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (0.534 g, 3.2 mmol) and 5-fluoropyrid-2-ylamidoxime (0.5 g, 3.2 mmol) in pyridine (5 ml) they were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus and recrystallization from 2-propanol provided 370 mg (43%) of 3- (5-fluoropyrid.2.il) -5- (3-cyanophenyl) -1,2,4-oxadiazole: GC / EI-MS provided m / z (rel. Int.) 266 (M +, 100), 267 (10), 138 (80), 114 (8), 102 (19), 96 (22), 76 (17), 57 (8).

3-(5-fluoropirid-2-il)-5-(3-ciano-5-fluorofenil)-1,2,4-oxadioazol (B31)3- (5-fluoropyrid-2-yl) -5- (3-cyano-5-fluorophenyl) -1,2,4-oxadioazol (B31)

3131 

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Se trató ácido 3-fluoro-5-cianobenzoico (1,0 g, 6 mmol) con una disolución de cloruro de oxalilo (12 ml de 2,5 M en diclorometano, 30 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante 2,5 horas. El exceso de cloruro de oxalilo se eliminó a vacío par proporcionar cloruro de 3-fluoro-5-cianobenzoílo.3-Fluoro-5-cyanobenzoic acid (1.0 g, 6 mmol) was treated with a solution of oxalyl chloride (12 ml of 2.5 M in dichloromethane, 30 mmol) and a catalytic amount of N, N- dimethylformamide . The reaction was stirred at room temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to provide 3-fluoro-5-cyanobenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-fluoro-5-cianobenzoílo (1,1 g, 6 mmol) y 5-fluoropirid-2-ilaminodoxima (0,93 g, 6 mmol) en piridina (5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar y la recristalización a partir de 2-propanol proporcionaron se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar y la recristalización a partir de 2-propanol proporcionaron 0,41 g/24%) de 3-(5-fluoropirid-2-il)-5-(3-ciano-5-fluorofenil)-1,2,4-oxadioazol: GC/IE-EM proporcionó m/z (rel. int.) 284 (M^{+}, 100), 285 (16), 253 (2), 138 (99), 120 (23), 108 (16), 96 (25), 82 (15), 57 (11).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-fluoro-5-cyanobenzoyl chloride (1.1 g, 6 mmol) and 5-fluoropyrid-2-ylaminodoxime (0.93 g, 6 mmol) in pyridine (5 ml) were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus and recrystallization from 2-propanol provided were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus and recrystallization from 2-propanol provided 0.41 g / 24%) of 3- (5-fluoropyrid-2-yl) -5- (3-cyano-5-fluorophenyl) -1.2, 4-oxadioazole: GC / IE-MS provided m / z (rel. Int.) 284 (M +, 100), 285 (16), 253 (2), 138 (99), 120 (23), 108 (16), 96 (25), 82 (15), 57 (11).

3-(3-fluoropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadioazol (B32)3- (3-fluoropyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadioazole (B32)

3232 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, cloruro de 3-cianobenzoílo (107 mg, 0,64 mmol) y 3-fluropirid-2-ilamidoxima (0,1 g, 0,64 mmol) en piridina (5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar, cromatografía en gel de sílice y recristalización a partir de 2-propanol proporcionaron 32 mg (19%) de 3-(3-fluoropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadioazol: GC/IE-EM proporcionó m/z (rel. int.) 266 (M^{+}, 75), 267 (12), 138 (100), 114 (11), 102 (19), 96 (17), 76 (16), 57 (5), 51 (5).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (107 mg, 0.64 mmol) and 3-fluropyrid-2-ylamidoxime (0.1 g, 0.64 mmol) in Pyridine (5 ml) was heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus, silica gel chromatography and recrystallization from 2-propanol provided 32 mg (19%) of 3- (3-fluoropyrid-2-yl) -5- (3-cyanophenyl) -1,2,4 -oxadioazole: GC / IE-MS provided m / z (rel. int.) 266 (M +, 75), 267 (12), 138 (100), 114 (11), 102 (19), 96 (17), 76 (16), 57 (5), 51 (5).

3-(3-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol (B33)3- (3-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole (B33)

3333 

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Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3,5-dimetoxibenzoílo (0,10 g, 0,5 mmol) y 5-fluoropirid-2-ilamidoxima (78 mg, 0,5 mmol) en piridina (3 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar, cromatografía en gel de sílice y recristalización a partir de 2-propanol proporcionaron 94 mg (62%) de 3-(3-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol: GC/IE-EM proporcionó m/z (rel. int.) 301 (M^{+}, 100), 302 (17), 165 (41), 137 (23), 122 (27), 96 (15), 77 (11), 63 (12).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3,5-dimethoxybenzoyl chloride (0.10 g, 0.5 mmol) and 5-fluoropyrid-2-ylamidoxime (78 mg, 0.5 mmol) in pyridine (3 ml) were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus, silica gel chromatography and recrystallization from 2-propanol provided 94 mg (62%) of 3- (3-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl) -1.2 , 4-oxadiazole: GC / IE-MS provided m / z (rel. Int.) 301 (M +, 100), 302 (17), 165 (41), 137 (23), 122 (27) , 96 (15), 77 (11), 63 (12).

3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol (B34)3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole (B34)

343. 4

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-cianobenzoílo (79 mg, 0,47 mmol) y 5-metoxipirid-2-ilamidoxima (79 mg, 0,47 mmol) en piridina (2,5 ml) se calentaron en un tubo sellado a 175ºC durante 4 horas. Un estímulo estándar, cromatografía en gel de sílice y recristalización a partir de 2-propanol proporcionaron 59 mg (45%) de 3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol: GC/IE-EM proporcionó m/z (rel. int.) 278 (M^{+}, 100), 279 (16), 150 (56), 128 (7), 107 (21), 102 (17), 80 (12), 64 (5).Using the general procedure for the synthesis of 1,2,4-oxadiazoles, 3-cyanobenzoyl chloride (79 mg, 0.47 mmol) and 5-methoxypyrid-2-ylamidoxime (79 mg, 0.47 mmol) in pyridine (2.5 ml) were heated in a sealed tube at 175 ° C for 4 hours. A standard stimulus, silica gel chromatography and recrystallization from 2-propanol provided 59 mg (45%) of 3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4 -oxadiazole: GC / IE-MS provided m / z (rel. int.) 278 (M +, 100), 279 (16), 150 (56), 128 (7), 107 (21), 102 (17), 80 (12), 64 (5).

3-(2-quinolinil)-5-(3-cianofenil)-1,2,4-oxadiazol (B35)3- (2-quinolinyl) -5- (3-cyanophenyl) -1,2,4-oxadiazole (B35)

3535

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-cianobenzoílo (68 mg, 0,41 mmol) y quinol-2-ilamidoxima (75,8 mg, 0,405 mol) en piridina (0,5 ml) se calentaron en un tubo sellado a 165ºC durante 22 horas. Un estímulo estándar, cromatografía en gel de sílice y recristalización a partir de etanol, y extracción de fase sólida (SPE) proporcionaron 23,7 mg (20%) de 3-(2-quinolinil)-5-(3-cianofenil)-1,2,4-oxadiazol. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,62 (s, 1H), 8,54 (d, 1H), 8,36 (d, 2H), 8,28 (d, 1H), 7,90 (d, 2H), 7,80 (t, 1H), 7,72 (t, 1H), 7,64 (t, 1H).Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 3-cyanobenzoyl (68 mg, 0.41 mmol) and quinol-2-ylamidoxime (75.8 mg, 0.405 mol) in pyridine (0.5 ml) were heated in a sealed tube at 165 ° C for 22 hours A standard stimulus, gel chromatography of silica and recrystallization from ethanol, and phase extraction solid (SPE) provided 23.7 mg (20%) of 3- (2-quinolinyl) -5- (3-cyanophenyl) -1,2,4-oxadiazole. 1 H NMR (CDCl 3), δ (ppm): 8.62 (s, 1H), 8.54 (d, 1H), 8.36 (d, 2H), 8.28 (d, 1H), 7.90 (d, 2H), 7.80 (t, 1H), 7.72 (t, 1H), 7.64 (t, 1H).

3-(3-cloro-5-trifluorometilpirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol (B36)3- (3-Chloro-5-trifluoromethylpyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole (B36)

3636

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-cianobenzoílo (66 mg, 0,40 mmol) y 3-cloro-5-trifluorometilpirid-2-ilamidoxima (96,5 mg, 0,403 mmol) en piridina (0,5 ml) se calentaron en un tubo sellado a 165ºC durante 22 horas. Un estímulo estándar y una extracción de fase sólida (SPE) proporcionaron 45,9 mg (33%) de 3-(3-cloro-5-trifluorometilpirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,99 (s, 1H), 8,57 (s, 1H), 8,49 (d, 1H), 8,19 (s, 1H), 7.92 (d, 1H), 7,72 (t, 1H).Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 3-cyanobenzoyl (66 mg, 0.40 mmol) and 3-Chloro-5-trifluoromethylpyrid-2-ylamidoxime (96.5 mg, 0.403 mmol) in pyridine (0.5 ml) were heated in a tube sealed at 165 ° C for 22 hours. A standard stimulus and a solid phase extraction (SPE) provided 45.9 mg (33%) of 3- (3-Chloro-5-trifluoromethylpyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole. 1 H NMR (CDCl 3), δ (ppm): 8.99 (s, 1H), 8.57 (s, 1H), 8.49 (d, 1H), 8.19 (s, 1H), 7.92 (d, 1H), 7.72 (t, 1H).

3-(2-piridil)-5-(5-cloro-2-metoxifenil)-1,2,4-oxadiazol (B37)3- (2-pyridyl) -5- (5-chloro-2-methoxyphenyl) -1,2,4-oxadiazole (B37)

3737

El ácido 5-cloro-O-anísico (187 mg, 1 mmol) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante dos horas. El cloruro de oxalilo en exceso se eliminó al vacío proporcionando cloruro de 5-cloro-2-metoxibenzoílo.The 5-chloro- O- anisic acid (187 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature for two hours. The excess oxalyl chloride was removed in vacuo to provide 5-chloro-2-methoxybenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 5-cloro-2-metoxibenzoílo y pirid-2-ilaminotoxima (137 mg, 1mmol) en piridina (1 ml) se calentaron a 115ºC durante 17 horas. Un estímulo estándar y cromatografía en gel de sílice proporcionaron 49 mg (17%) de 3-(2-piridil)-5-(5-cloro-2-metoxifenil)-1,2,4-oxadiazol. RMN-^{1}H (CDCl_{3}), \delta (ppm): 4,00 (s, 3H), 7,03 (d, J = 8,9 Hz, 1H), 7,42-7,47 (m, 1H), 7,50 (dd, J = 8,9 Hz, 2,8 Hz, 1H), 7,87 (ddd, J = 1,4 Hz, 8,2 Hz, 1H), 8,22 (d, J = 8,2 Hz, 1H), 8,28 (d, J = 2,4 Hz, 1H), 8,84 (m, 1H).Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 5-chloro-2-methoxybenzoyl and pyrid-2-ylaminotoxime (137 mg, 1mmol) in pyridine (1 ml) was heated at 115 ° C for 17 hours. A standard stimulus and silica gel chromatography provided 49 mg (17%) of 3- (2-pyridyl) -5- (5-chloro-2-methoxyphenyl) -1,2,4-oxadiazole. 1 H NMR (CDCl 3), δ (ppm): 4.00 (s, 3H), 7.03 (d, J = 8.9 Hz, 1H), 7.42-7.47 (m, 1H), 7.50 (dd, J = 8.9 Hz, 2.8 Hz, 1H), 7.87 (ddd, J = 1.4 Hz, 8.2 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.84 (m, 1 HOUR).

3-(2-piridil)-5-(2,3-dimetoxifenil)-1,2,4-oxadiazol (B38)3- (2-pyridyl) -5- (2,3-dimethoxyphenyl) -1,2,4-oxadiazole (B38)

3838

El ácido 2,3-dimetoxibenzoico (182 mg, 1 mmol) se trató con una disolución de cloruro de oxalilo (1,5 ml, de 2 M en diclorometano, 3mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante 2 horas. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 2,3-dimetoxibenzoílo.2,3-Dimethoxybenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 ml, 2M in dichloromethane, 3mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to afford 2,3-dimethoxybenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 2,3-dimetoxibenzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 115ºC durante 17 horas. Un estímulo estándar y cromatografía en gel de sílice proporcionaron 120 mg (42%) de 3-(2-piridil)-5-(2,3-dimetoxixifenil)-1,2,4-oxadiazol.Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 2,3-dimethoxybenzoyl and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) they were heated at 115 ° C for 17 hours. A standard stimulus and silica gel chromatography provided 120 mg (42%) of 3- (2-pyridyl) -5- (2,3-dimethoxyphenyl) -1,2,4-oxadiazole.

3-(2-piridil)-5-(2-cloro-5-metiltiofenil)-1,2,4-oxadiazol (B39)3- (2-pyridyl) -5- (2-chloro-5-methylthiophenyl) -1,2,4-oxadiazole (B39)

3939

El ácido 2-cloro-5-metiltiobenzoico (182 mg, 1 mmol) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante 2 horas. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 2-cloro-5-metiltiobenzoílo.2-Chloro-5-methylthiobenzoic acid (182 mg, 1 mmol) was treated with a solution of oxalyl chloride (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature for 2 hours. The excess oxalyl chloride was removed in vacuo to provide 2-chloro-5-methylthiobenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 2,3-dimetoxibenzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 115ºC durante 17 horas. Un estímulo estándar y cromatografía en gel de sílice proporcionaron 250 mg (82%) de 3-(2-piridil)-5-(2-cloro-5-metiltiofenil)-1,2,4-oxadiazol. RMN-^{1}H (CDCl_{3}), \delta (ppm): 7,37 (dd, J = 3,4 Hz, 8,2 Hz, 1H), 8,23 (dd, J = 2,2 Hz, 8,0 Hz 1 x H), 8,85 (m, 1H).Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 2,3-dimethoxybenzoyl and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) they were heated at 115 ° C for 17 hours. A standard stimulus and silica gel chromatography provided 250 mg (82%) of 3- (2-pyridyl) -5- (2-chloro-5-methylthiophenyl) -1,2,4-oxadiazole. 1 H NMR (CDCl 3), δ (ppm): 7.37 (dd, J = 3.4 Hz, 8.2 Hz, 1H), 8.23 (dd, J = 2.2 Hz, 8.0 Hz 1 x H), 8.85 (m, 1H).

3-(2-piridil)-5-(3-fenoxifenil)-1,2,4-oxadiazol (B40)3- (2-pyridyl) -5- (3-phenoxyphenyl) -1,2,4-oxadiazole (B40)

4040

El ácido 3-fenoxibenzoico (214 mg, 1,0 mmol) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante toda una noche. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 3-fenoxibenzoílo.3-Phenoxybenzoic acid (214 mg, 1.0 mmol) was treated with a solution of oxalyl chloride (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature overnight. The excess oxalyl chloride was removed in vacuo to provide 3-phenoxybenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-fenoxibenzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en un vial sellado durante toda una noche a 110ºC. Un estímulo estándar proporcionó 118 mg (37ºC) de 3-(2-piridil)-5-(3-fenoxifenil)-1,2,4-oxadiazol como un sólido blanco.Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 3-phenoxybenzoyl and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) they were heated in a sealed vial for a whole night at 110 ° C. A standard stimulus provided 118 mg (37 ° C) of 3- (2-pyridyl) -5- (3-phenoxyphenyl) -1,2,4-oxadiazole Like a white solid

3-(2-piridil)-5-(3-benzoilfenil)-1,2,4-oxadiazol (B41)3- (2-pyridyl) -5- (3-benzoylphenyl) -1,2,4-oxadiazole (B41)

4141

El ácido 3-benzoilbenzoico (226 mg, 1,0 mmol) es diclorometano (1,5 ml) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante toda una noche. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 3-benzoilbenzoílo.3-Benzoylbenzoic acid (226 mg, 1.0 mmol) is dichloromethane (1.5 ml) treated with an oxalyl chloride solution (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature overnight. The excess oxalyl chloride was removed in vacuo to provide 3-benzoylbenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3-benzoilbenzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en un vial sellado durante toda una noche a 110ºC. Un estímulo estándar proporcionó 200 mg (61%) de 3-(2-piridil)-5-(3-benzoilfenil)-1,2,4-oxadiazol como un sólido blanco. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,85 (d, 1H), 8,68 (m, 1 H), 8,53 (dd, 1H), 8,23/d, 1H), 8,07 (m, 1H), 7,88 (m, 3H), 7,70 (m, 2H), 7,49 (m, 3H).Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 3-benzoylbenzoyl and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) they were heated in a sealed vial for a whole night at 110 ° C. A standard stimulus provided 200 mg (61%) of 3- (2-pyridyl) -5- (3-benzoylphenyl) -1,2,4-oxadiazole Like a white solid 1 H NMR (CDCl 3), δ (ppm): 8.85 (d, 1H), 8.68 (m, 1 H), 8.53 (dd, 1H), 8.23 / d, 1H), 8.07 (m, 1H), 7.88 (m, 3H), 7.70 (m, 2H), 7.49 (m, 3H).

3-(2-piridil)-5-(2-bromo-5-metoxifenil)-1,2,4-oxadiazol (B42)3- (2-pyridyl) -5- (2-bromo-5-methoxyphenyl) -1,2,4-oxadiazole (B42)

4242 

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El ácido 2-bromo-5-metoxibenzoico (231 m, 1,0 mmol) en diclorometano (1,5 ml) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante toda una noche. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 2-bromo-5-metoxibenzoílo.2-Bromo-5-methoxybenzoic acid (231 m, 1.0 mmol) in dichloromethane (1.5 ml) was treated with a solution of oxalyl chloride (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature overnight. The excess oxalyl chloride was removed in vacuo to provide 2-bromo-5-methoxybenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 2-bromo-5-metoxibenzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en un vial sellado durante toda una noche a 110ºC. Un estímulo estándar y filtración en gel de sílice proporcionaron 147 mg (44%) de 3-(2-piridil)-5-(2-bromo-5-metoxifenil)-1,2,4-oxadiazol. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,85 (d, 1H), 8,24 (d, 1H), 7,89 (m, 1H), 7,65 (m, 2H), 7,47 (m, 1H), 6,99 (m, 1H), 3,89 (s, 3H).Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 2-bromo-5-methoxybenzoyl and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated in a sealed vial for overnight at 110 ° C. A standard stimulus and gel filtration of silica provided 147 mg (44%) of 3- (2-pyridyl) -5- (2-bromo-5-methoxyphenyl) -1,2,4-oxadiazole. 1 H NMR (CDCl 3), δ (ppm): 8.85 (d, 1H), 8.24 (d, 1H), 7.89 (m, 1H), 7.65 (m, 2H), 7.47 (m, 1H), 6.99 (m, 1H), 3.89 (s, 3H).

3-(2-piridil)-5-(2-cloro-5-(trifluorometil)fenil)-1,2,4-oxadiazol (B43)3- (2-pyridyl) -5- (2-chloro-5- (trifluoromethyl) phenyl) -1,2,4-oxadiazole (B43)

4343

El ácido 2-cloro-5-(trifluorometil)benzoico (224 mg, 1,0 mmol) en diclorometano (1,5 ml) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformami-
da. La reacción se agitó a temperatura ambiente durante toda una noche. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 2-cloro-5-(trifluorometil)benzoílo.2-Chloro-5- (trifluoromethyl) benzoic acid (224 mg, 1.0 mmol) in dichloromethane (1.5 ml) was treated with a solution of oxalyl chloride (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N- dimethylformami-
gives. The reaction was stirred at room temperature overnight. The excess oxalyl chloride was removed in vacuo to provide 2-chloro-5- (trifluoromethyl) benzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 2-cloro-5-(trifluorometil)benzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en un vial sellado durante toda una noche a 110ºC. Un estímulo estándar y filtración en gel de sílice proporcionaron 136 mg (42%) de 3-(2-piridil)-5-(2-cloro-5-(trifluorometil)fenil)-1,2,4-oxadiazol como un sólido ocre. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,87 (d, 1H), 8,56 (s, 1H), 8,25 (d, 1H), 7,89 (m, 1H), 7,78 (m, 2H), 7,50 (m, 1H).Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 2-Chloro-5- (trifluoromethyl) benzoyl and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) were heated in a sealed vial for overnight at 110 ° C. A standard stimulus and gel filtration of silica provided 136 mg (42%) of 3- (2-pyridyl) -5- (2-chloro-5- (trifluoromethyl) phenyl) -1,2,4-oxadiazole As an ocher solid. 1 H NMR (CDCl 3), δ (ppm): 8.87 (d, 1H), 8.56 (s, 1H), 8.25 (d, 1H), 7.89 (m, 1H), 7.78 (m, 2H), 7.50 (m, 1H).

3-(2-piridil)-5-(3,4,5-trifluorofenil)-1,2,4-oxadiazol (B44)3- (2-pyridyl) -5- (3,4,5-trifluorophenyl) -1,2,4-oxadiazole (B44)

4444

El ácido 3,4,5-trifuorobenzoico (0,176 g, 1,0 mmol) en diclorometano (1,5 ml) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante toda una noche. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 3,4,5-trifluorobenzoílo.3,4,5-Trifuorobenzoic acid (0.176 g, 1.0 mmol) in dichloromethane (1.5 ml) was treated with a solution of oxalyl chloride (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N- dimethylformamide. The reaction was stirred at room temperature overnight. The excess oxalyl chloride was removed in vacuo to provide 3,4,5-trifluorobenzoyl chloride.

Usando el procedimiento general para la síntesis de 1,2,4-oxadiazoles, el cloruro de 3,4,5-trifluorobenzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en un vial sellado durante toda una noche a 110ºC. Un estímulo estándar y cromatografía en gel de sílice (con 10-30% de acetato de etilo en hexano) proporcionaron 15 mg (5%) de 3-(2-piridil)-5-(3,4,5-trifluorofenil)-1,2,4-oxadiazol como un sólido blanco.Using the general procedure for synthesis of 1,2,4-oxadiazoles chloride 3,4,5-trifluorobenzoyl and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) they were heated in a sealed vial for a whole night at 110 ° C. A standard stimulus and silica gel chromatography (with 10-30% ethyl acetate in hexane) provided 15 mg (5%) of 3- (2-pyridyl) -5- (3,4,5-trifluorophenyl) -1,2,4-oxadiazole Like a white solid

3-(2-piridil)-5-(2,5,6-trifluorofenil)-1,2,4-oxadiazol (B45)3- (2-pyridyl) -5- (2,5,6-trifluorophenyl) -1,2,4-oxadiazole (B45)

45Four. Five

El ácido 2,5,6-trifuorobenzoico (0,176 g, 1,0 mmol) se trató con una disolución de cloruro de oxalilo (1,5 ml de 2 M en diclorometano, 3 mmol) y una cantidad catalítica de N,N-dimetilformamida. La reacción se agitó a temperatura ambiente durante 16 horas. El exceso de cloruro de oxalilo se eliminó a vacío proporcionando cloruro de 2,5,6-trifluorobenzoílo.2,5,6-Trifuorobenzoic acid (0.176 g, 1.0 mmol) was treated with a solution of oxalyl chloride (1.5 ml of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N, N - dimethylformamide The reaction was stirred at room temperature for 16 hours. The excess oxalyl chloride was removed in vacuo to provide 2,5,6-trifluorobenzoyl chloride.

Una disolución del intermedio cloruro de 2,5,6-trifluorobenzoílo y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron en un vial sellado durante 0,5 horas. La cromatografía en gel de sílice proporcionó 151 mg (51%) de N-[(2,5,6-trifluorobenzoílo)oxi]piridina-2-carboximidamina.A solution of the intermediate 2,5,6-trifluorobenzoyl chloride and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) was heated in a sealed vial for 0.5 hours. Silica gel chromatography provided 151 mg (51%) of N - [(2,5,6-trifluorobenzoyl) oxy] pyridine-2-carboximidamine.

Una disolución de N-[(2,5,6-trifluorobenzoíl)oxi]piridina-2-carboximidamida (50 mg, 0,169 mmol) en piridina (0,3 ml) se calentó a115ºC durante 17 horas. Un estímulo estándar, y cromatografía en gel de sílice, proporcionaron 9,5 mg (20%) de 3-(2-piridil)-5-(2,5,6-triflurofenil)-1,2,4-oxadiazol.A solution of N - [(2,5,6-trifluorobenzoyl) oxy] pyridine-2-carboximidamide (50 mg, 0.169 mmol) in pyridine (0.3 ml) was heated at 115 ° C for 17 hours. A standard stimulus, and silica gel chromatography, provided 9.5 mg (20%) of 3- (2-pyridyl) -5- (2,5,6-triflurophenyl) -1,2,4-oxadiazole.

Ejemplo 4Example 4 Síntesis de 1,2,4-oxadiazoles 3,5-disustituidos a partir de aclimidazolesSynthesis of 1,2,4-oxadiazoles 3,5-disubstituted from aclimidazoles 

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3-(3-metoxifenil)-5-(2-piridil)-1,2,4-oxadiazol (B8)3- (3-methoxyphenyl) -5- (2-pyridyl) -1,2,4-oxadiazole (B8)

4646 

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Usando modificaciones del procedimiento de Shine y col., J.Heterocyclic Chem. (1989) 26:125-128, se trató una disolución de ácido picolínico (123 mg, 1 mmol) en piridina (1 ml) se trató con 1,1'-carbonildiimidazol (162 mg, 1 mmol) y la reacción se agitó a temperatura ambiente hasta que la evolución de dióxido de carbono se terminó (30 min.). El intermedio acrilimidazol se trató después con 3-metoxibenzamidoxima (166 mg, 1 mmol), y la reacción se calentó a reflujo durante 1 hora. Se añadió agua helada a la mezcla de reacción para precipitar el oxadiazol. El sólido se recogió mediante filtración, se lavó con agua y se secó proporcionando 80 mg (32%) de 3-(3-metoxifenil)-5-(2-piridil)-1,2,4-oxadiazol: p.f.:90-94ºC; GC/IE-EM proporcionó m/z (rel. int.) 253 (M^{+},100), 254 (17), 179 (2), 175 (2). 149 (77), 133 (33), 119 (4), 106 (29), 78 (45), 51 (18).Using modifications of the procedure of Shine et al., J. Heterocyclic Chem . (1989) 26 : 125-128, a solution of picolinic acid (123 mg, 1 mmol) in pyridine (1 ml) was treated with 1,1'-carbonyldiimidazole (162 mg, 1 mmol) and the reaction stirred at room temperature until the evolution of carbon dioxide was finished (30 min.). The acrylimidazole intermediate was then treated with 3-methoxybenzamidoxime (166 mg, 1 mmol), and the reaction was heated at reflux for 1 hour. Ice water was added to the reaction mixture to precipitate the oxadiazole. The solid was collected by filtration, washed with water and dried to provide 80 mg (32%) of 3- (3-methoxyphenyl) -5- (2-pyridyl) -1,2,4-oxadiazole: mp: 90- 94 ° C; GC / IE-EM provided m / z (int. Rel.) 253 (M +, 100), 254 (17), 179 (2), 175 (2). 149 (77), 133 (33), 119 (4), 106 (29), 78 (45), 51 (18).

Ejemplo 5Example 5 Síntesis de 1,2,4-oxadiazoles 3,5-disustituidos a partir de ésteresSynthesis of 1,2,4-oxadiazoles 3,5-disubstituted from esters 

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3-(pirid-2-il)-5-(2-hidroxifenil)-1,2,4-oxadiazol (B46)3- (pyrid-2-yl) -5- (2-hydroxyphenyl) -1,2,4-oxadiazole (B46)

4747 

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Usando el procedimiento de Korbonits y col., J. Chem. Soc. Perkin. Trans. 1 (1982) 759-766, se trató a reflujo una mezcla de salicilato de etilo (200 mg, 1,2 mmol), pirid-2-ilamidoxima (82,5 mg, 0,6 mmol), etóxido de sodio al 21% (19,4 ml, 6 mmol) en etanol (12 ml) durante 16 horas. Después de enfriar, la mezcla de reacción se diluyó con diclorometano (50 ml) y se lavó con agua e hidrocarbonato de sodio saturado. La fase orgánica se secó con sulfato de sodio y se concentró al vacío. La recristalización a partir de éter dietílico proporcionó 15 mg (5%) de 3-(pirid-2-il)-5-(2-hidroxifenil)-1,2,4-oxadiazol.Using the procedure of Korbonits et al., J. Chem. Soc. Perkin. Trans. 1 (1982) 759-766, a mixture of ethyl salicylate (200 mg, 1.2 mmol), pyrid-2-ylamidoxime (82.5 mg, 0.6 mmol), sodium ethoxide 21 was treated under reflux % (19.4 ml, 6 mmol) in ethanol (12 ml) for 16 hours. After cooling, the reaction mixture was diluted with dichloromethane (50 ml) and washed with water and saturated sodium hydrocarbonate. The organic phase was dried with sodium sulfate and concentrated in vacuo. Recrystallization from diethyl ether provided 15 mg (5%) of 3- (pyrid-2-yl) -5- (2-hydroxyphenyl) -1,2,4-oxadiazole. 

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3-(2-piridil)-5-(5-cloro-2-hidroxifenil)-1,2,4-oxadiazol (B47)3- (2-pyridyl) -5- (5-chloro-2-hydroxyphenyl) -1,2,4-oxadiazole (B47)

4848 

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En una forma similar, 5-cloro-2-hidroxibenzoato de metilo (372 mg, 2 mmol), pirid-2-ilamidoxima (137 mg, 1 mmol), etóxido de sodio al 21% (32,4 ml, 10 mmol) en etanol (20 ml) se calentaron a reflujo durante 16 horas. Un estímulo estándar, y recristalización a partir de éster dietílico produjo 14,2 mg (5%) de 3-(2-piridil)-5-(5-cloro-2-hidroxifenil)-1,2,4-oxadiazol.In a similar way, 5-chloro-2-hydroxybenzoate methyl (372 mg, 2 mmol), pyrid-2-ylamidoxime (137 mg, 1 mmol), 21% sodium ethoxide (32.4 ml, 10 mmol) in ethanol (20 ml) they were heated at reflux for 16 hours. A standard stimulus, and recrystallization from diethyl ester produced 14.2 mg (5%) of 3- (2-pyridyl) -5- (5-chloro-2-hydroxyphenyl) -1,2,4-oxadiazole.

Ejemplo 6Example 6 Síntesis de 1,2,4-oxadiazoles 3,5-disustituidos a partir de anhídridos isatoicosSynthesis of 1,2,4-oxadiazoles 3,5-disubstituted from anhydrides isatoic

3-(2-piridil)-5-(5-cloro-2-hidroxifenil)-1,2,4-oxadiazol (B48)3- (2-pyridyl) -5- (5-chloro-2-hydroxyphenyl) -1,2,4-oxadiazole (B48)

4949 

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Usando modificaciones del procedimiento de Nagahara y col., Chem. Phar., Bull., (1975) 23: 3178-3183, una mezcla de anhídrido isatoico (163 mg, 1 mmol) y pirir-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentó a 115ºC durante 17 horas. Después de enfriar la reacción, la mezcla se diluye con 50 ml de diclorometano y se lavó con agua e hidrocarbonato de sodio saturado. La fase orgánica se secó sobre sulfato de sodio, se filtró a través de gel de sílice y se concentró al vacío. La recristalización a partir de éster dietílico proporcionó 45,6 mg (19%) de 3-(2-piridil)-5-(2-aminofenil)-1,2,4-oxadiazol.Using modifications of the procedure of Nagahara et al., Chem. Phar., Bull ., (1975) 23: 3178-3183, a mixture of isatoic anhydride (163 mg, 1 mmol) and pyrir-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) was heated at 115 ° C for 17 hours. After cooling the reaction, the mixture is diluted with 50 ml of dichloromethane and washed with water and saturated sodium hydrocarbonate. The organic phase was dried over sodium sulfate, filtered through silica gel and concentrated in vacuo. Recrystallization from diethyl ester provided 45.6 mg (19%) of 3- (2-pyridyl) -5- (2-aminophenyl) -1,2,4-oxadiazole.

3-(2-piridil)-5-(2-aminofenil)-1,2,4-oxadiazol (B49)3- (2-pyridyl) -5- (2-aminophenyl) -1,2,4-oxadiazole (B49)

50fifty 

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En una forma similar, anhídrido 5-cloroisatoico (197 mg, 1 mmol) y pirid-2-ilamidoxima (137 mg, 1 mmol) en piridina (1 ml) se calentaron a 115ºC durante 17 horas. Un estímulo proporcionó 138 mg (51%) de 3-(2-piridil)-5-(2-aminofenil)-1,2,4-oxadiazol.In a similar way, anhydride 5-Chloroisate (197 mg, 1 mmol) and pyrid-2-ylamidoxime (137 mg, 1 mmol) in pyridine (1 ml) they were heated at 115 ° C for 17 hours. A stimulus provided 138 mg (51%) of 3- (2-pyridyl) -5- (2-aminophenyl) -1,2,4-oxadiazole.

Ejemplo 7Example 7 Síntesis de 1,3-oxazoles 2,4-disustituidosSynthesis of 1,3-oxazoles 2,4-disubstituted

2-[3-clorofenil]-4-[piridin-2-il]-1,3-oxazol (B50)2- [3-chlorophenyl] -4- [pyridin-2-yl] -1,3-oxazole (B50)

5151 

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Usando los procedimientos de Kelly y col., J. Org. Chem., (1996) 61: 4623-4633, una disolución de 2-bromoacetilpiridina (120 mg, 0,6 mmol) en tolueno (5 ml) se trató con 3-clorobenzamida (300 mg, 1,9 mmol) y la mezcla se calentó en un vial sellado a reflujo durante 60 horas. La mezcla se enfrió después y el disolvente se eliminó a vacío. La cromatografía en gel de sílice que usa un gradiente de hexano a acetato de etilo proporcionó 38 mg (9%) de 2-[clorofenil]-4-[piridin-2-il]-1,3-oxazol como un sólido pálido amarillo. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,62 (d, 1H), 8,35 (s, 1H), 8,15 (m, 1H), 8,00 (m, 2H), 7,80 (td, 1H), 7,42 (m, 2H), 7,23 (m, 1H).Using the procedures of Kelly et al., J. Org. Chem ., (1996) 61 : 4623-4633, a solution of 2-bromoacetylpyridine (120 mg, 0.6 mmol) in toluene (5 ml) was treated with 3-chlorobenzamide (300 mg, 1.9 mmol) and the The mixture was heated in a sealed vial at reflux for 60 hours. The mixture was then cooled and the solvent removed in vacuo. Silica gel chromatography using a gradient of hexane to ethyl acetate provided 38 mg (9%) of 2- [chlorophenyl] -4- [pyridin-2-yl] -1,3-oxazole as a pale yellow solid . 1 H NMR (CDCl 3), δ (ppm): 8.62 (d, 1H), 8.35 (s, 1H), 8.15 (m, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.42 (m, 2H), 7.23 (m, 1H).

2-[3-bromofenil]-4-[piridin-2-il]-1,3-oxazol (B51)2- [3-bromophenyl] -4- [pyridin-2-yl] -1,3-oxazole (B51)

5252

En una forma similar 2-bromoacetilpiridina (500 mg, 2,5 mmol) y 3-clorobenzamida (1,2 g, 6 mmol) en tolueno (10 ml) se calentó en un vial sellado a reflujo durante 60 horas. Un estímulo y la cromatografía en gel de sílice que usa un gradiente de hexano a acetato de etilo proporcionaron 50 mg (7%) de 2-[3-bromofenil]-4-[piridin-2-il]-1,3-oxazol como un sólido blanco. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,60 (d, 1H), 8,34 (s, 1H), 8,30/t, 1H), 8,00 (m, 2H), 7,80 (td, 1H), 7,60 (dd, 1H), 7,35 (t, 1H), 7,23 (m, 1H).in a similar way 2-Bromoacetylpyridine (500 mg, 2.5 mmol) and 3-Chlorobenzamide (1.2 g, 6 mmol) in toluene (10 ml) It was heated in a sealed vial at reflux for 60 hours. A stimulus and silica gel chromatography using a gradient of hexane to ethyl acetate provided 50 mg (7%) of 2- [3-bromophenyl] -4- [pyridin-2-yl] -1,3-oxazole Like a white solid 1 H NMR (CDCl 3), δ (ppm): 8.60 (d, 1H), 8.34 (s, 1H), 8.30 / t, 1H), 8.00 (m, 2H), 7.80 (td, 1H), 7.60 (dd, 1H), 7.35 (t, 1H), 7.23 (m, 1H).

2-[3-cianofenil]-4-[piridin-2-il]-1,3-oxazol (B52)2- [3-cyanophenyl] -4- [pyridin-2-yl] -1,3-oxazole (B52)

5353

Una mezcla de 2-[3-bromofenil]-4-[piridin-2-il]-1,3-oxazol (23 mg, 0,076 mmol) y cianuro de cinc (112 mg, 0,96 mmol) en N,N-dimetilformamida (2 ml) se trató con Pd(PPh_{3})_{4} (74 mg, 0,064 mmol) y se calentó durante toda una noche a 80ºC. Un estímulo estándar y cromatografía proporcionaron 6 mg (32%) de 2-[3-cianofenil]-4-[piridin-2-il]-1,3-oxazol como un sólido blanco. RMN-^{1}H (CDCl_{3}), \delta (ppm): 8,61 (d, 1H), 8,45 (s, 1H), 8,38 (s, 1H), 8,36 (m, 1H), 8,00 (d, 1H), 7,80 (m, 2H), 7,61 (t, 1H), 7,23 (m, 1H).A mixture of 2- [3-bromophenyl] -4- [pyridin-2-yl] -1,3-oxazole (23 mg, 0.076 mmol) and zinc cyanide (112 mg, 0.96 mmol) in N, N -dimethylformamide (2 ml) was treated with Pd (PPh3) 4 (74 mg, 0.064 mmol) and heated overnight at 80 ° C. A standard stimulus and chromatography provided 6 mg (32%) of 2- [3-cyanophenyl] -4- [pyridin-2-yl] -1,3-oxazole as a white solid. 1 H NMR (CDCl 3), δ (ppm): 8.61 (d, 1H), 8.45 (s, 1H), 8.38 (s, 1H), 8.36 (m, 1H), 8.00 (d, 1H), 7.80 (m, 2H), 7.61 (t, 1H), 7.23 (m, 1H).

Ejemplo 8Example 8 Ensayos de actividad antagonista de receptor de Grupo IGroup I receptor antagonist activity assays Ensayo de Rasteo de AstrocitosAstrocyte Scratching Test

Los cultivos de astrocitos primarios se prepararon a partir de cachorros de rata Sprage-Dawley de 3 a 5 días de edad usando una modificación de Miller (Miller y col., J. Neuroscience, 15(9): 6103-6109, 1995). En breve, los cultivos primarios se plaquearon en matraces recubiertos de poli-L-lisina en medio de Eagle modificado por Dulbecco (DMEM) conteniendo suero fetal de ternera (FCS). Después de 6 días, los cultivos celulares se agitaron durante toda una noche a 280 rpm, después se transfirieron a medios definidos por astrocitos (ADM) que contienen factores de crecimiento que regulan al alza la expresión de mGluR5 (Miller y col., 1995). Para análisis de cubeta, estos cultivos se regularon al alza con factores de crecimiento en matraces durante 3-5 días, después se recogieron y prepararon para medida de movilización de [Ca^{2+}]_{i} como se describe previamente (Nemeth y col., 1998).Primary astrocyte cultures were prepared from Sprage-Dawley rat pups 3 to 5 days old using a Miller modification (Miller et al., J. Neuroscience, 15 (9) : 6103-6109, 1995). In brief, the primary cultures were plated in poly-L-lysine coated flasks in Dulbecco-modified Eagle's medium (DMEM) containing fetal calf serum (FCS). After 6 days, cell cultures were shaken overnight at 280 rpm, then transferred to astrocyte-defined media (ADM) containing growth factors that regulate the expression of mGluR5 (Miller et al., 1995). . For cuvette analysis, these cultures were upregulated with growth factors in flasks for 3-5 days, then collected and prepared for mobilization measurement of [Ca2 +] i as previously described ( Nemeth et al., 1998).

Para análisis de FLIPR, las células se sembraron en placas de 96 pocillos de fondo claro recubiertas con poli-D lisina con lados negros y se llevó a cabo análisis de movilización de [Ca^{2+}]_{i} 3 días después de la regulación al alza con factores de crecimiento. Los cultivos celulares en placas de 96 pocillos se cargaron con una disolución de 4 \muM en forma de éster de acetoximetilo del indicador de calcio fluorescente Fluo-3 (Molecular Probes, Eugene, Oregón) en Plurónico al 0,01%. Todos los ensayos se llevaron a cabo en un tampón que contiene NaCl 127 mM, KCl 5 mM, MgCl_{2}, NaH_{2}PO_{4} 0,7 nM, CaCl_{2} 2mM, NaHCO_{3} 0,422 mg/ml, HEPES 2,4 mg/ml, glucosa 1,8 mg/ml y BSA Fracción IV 1 mg/ml (pH 7,4).For FLIPR analysis, cells were seeded in 96-well light-bottomed plates coated with poly-D lysine with black sides and was carried out [Ca 2 +] mobilization analysis 3 days later of upward regulation with growth factors. Crops Cells in 96-well plates were loaded with a solution of 4 µM in the form of an acetoxymethyl ester of the calcium indicator Fluo-3 fluorescent (Molecular Probes, Eugene, Oregon) in Pluronic 0.01%. All trials were carried out. in a buffer containing 127 mM NaCl, 5 mM KCl, MgCl2, 0.7 nM NaH 2 PO 4, 2mM CaCl 2, 0.422 mg NaHCO 3, HEPES 2.4 mg / ml, glucose 1.8 mg / ml and BSA Fraction IV 1 mg / ml (pH 7.4).

Los experimentos FLPIR se hicieron usando un ajusta ajuste de láser de 0,800 W y una velocidad de obturador de cámara CCD de 0,4 segundos. Cada experimento FLIPR se inició con 180 \mul de tampón presente en cada pocillo de la placa celular. Una adición de 20 \mul de la placa de antagonista fue seguida una adición de 50 \mul de la placa de agonista. Después de cada adición la señal de fluorescencia se probó 30 veces a intervalos de 1 segundo seguidas por 3 pruebas a intervalos de 5 segundos. Las respuestas se midieron como la altura del pico de la respuesta en el periodo de prueba.FLPIR experiments were done using a Adjusts 0.800W laser setting and shutter speed of 0.4 second CCD camera. Each FLIPR experiment started with 180 µl of buffer present in each well of the cell plate. A addition of 20 µl of the antagonist plate was followed by adding 50 µl of the agonist plate. After every addition the fluorescence signal was tested 30 times at intervals of 1 second followed by 3 tests at intervals of 5 seconds. The responses were measured as the peak height of the response in the trial period.

Las determinaciones de CE_{50}/CI_{50} se hicieron a partir de los datos obtenidos de curvas de respuesta de concentración (CRC) de 8 puntos llevadas a cabo por duplicado. La CRC de agonista se generó ajustando todas las respuestas a escala de la máxima respuesta observada para la placa. El bloqueo con antagonista de la prueba de agonista se normalizó con respecto a la respuesta promedio de la prueba de agonista en 14 pocillos de control en la misma placa.The CE_ {50} / IC_ {50} determinations are made from the data obtained from response curves of concentration (CRC) of 8 points carried out in duplicate. The Agonist CRC was generated by adjusting all responses to the scale of the maximum response observed for the plate. Blocking with agonist test antagonist normalized with respect to the average agonist test response in 14 wells of control on the same board.

Ensayo de Rastreo de CaR/mGluR5dCaR / mGluR5d Tracking Test

Las células HEK 293 que expresan el receptor quimérico CaR/mGluR5d (línea celular clonal hCaR/
hmGluR5d_hek6) se plaquearon 24 antes del ensayo a una densidad de 100.000 células por pocillo en placas de fondo transparente, de 96 pocillos negros cubiertos por colágeno-I (Becton Dickenson) en DMEM suplementadas con FBS al 10%. (Hyclone).HEK 293 cells expressing the chimeric receptor CaR / mGluR5d (clonal cell line hCaR /
hmGluR5d_hek6) were plated 24 before the test at a density of 100,000 cells per well in transparent bottom plates, of 96 black wells covered by collagen-I (Becton Dickenson) in DMEM supplemented with 10% FBS. (Hyclone)

En el día del ensayo, el medio de cultivo de tejidos se aspira de los pocillos en una placa y se añaden a cada pocillo 80 \mul de Tampón de Ensayo (el Tampón de Ensayo es: HEPES 20 mM, NaCl 146 mM, KCl 5 mM, MgCl_{2} 1 mM, CaCl_{2} 1 mM, BSA 1 mg/ml, glucosa 1 mg/ml, pH 7,4) suplementado con 6 \muM de tinción sensible a Ca^{2+}, Fluo-3 AM 3 (Molecular Probes) y se añade a cada pocillo plurónico al 0,025% (Molecular Probes). La placa se incubó después en la oscuridad durante 1 hora a temperatura ambiente para cargar eficientemente las células con Fluo-3. Al final de la incubación, el Fluo-3 extracelular se elimina lavando la placa con tampón de Ensayo. El Tampón de Ensayo se añadió de nuevo a cada pocillo (volumen final = 160 \mul) antes de comenzar el ensayo.On the day of the test, the culture medium of tissues are aspirated from the wells in a plate and added to each well 80 µl of Assay Buffer (Assay Buffer is: HEPES 20 mM, 146 mM NaCl, 5 mM KCl, 1 mM MgCl 2, 1 mM CaCl 2, BSA 1 mg / ml, glucose 1 mg / ml, pH 7.4) supplemented with 6 µM of Ca 2+ sensitive staining, Fluo-3 AM 3 (Molecular Probes) and 0.025% pluronic well is added to each well (Molecular You try). The plate was then incubated in the dark for 1 hour at room temperature to efficiently charge cells with Fluo-3 At the end of the incubation, the Extracellular fluo-3 is removed by washing the plate with Assay buffer. The Test Buffer was added again to each well (final volume = 160 µl) before starting test.

La placa se cargó dentro de un dispositivo robótico FLIPR (Molecular Devices) con el ajuste de láser a 0,8 Watts. A un tiempo de 10 segundos después de la iniciación del ensayo, se añadieron a los 160 \mul de Tampón de Ensayo en cada pocillo de la placa 40 \mul de Tampón de Ensayo conteniendo 62,5 \muM de sustancia de prueba y DMSO al 2% proporcionando una concentración final de 12 \muM de sustancia de prueba y DMSO al 0,4%. A un tiempo de 75 segundos después de la iniciación del ensayo, se añadieron 50 \mul de Tampón de Ensayo que contienen CaCl_{2} 6 mM a los 200 \mul presentes en cada pocillo para producir una concentración final de Ca^{2+} de 2,0 mM, y una concentración final de sustancia de prueba de 10 nM. La intensidad de fluorescencia relativa (excitación \lambda = 488 nm/emisión \lambda = 510 nM) se somete a seguimiento a intervalos de tiempo relevantes durante todo el periodo de ensayo para medir la activación y/o inhibición del receptor.The board was loaded inside a device robotic FLIPR (Molecular Devices) with laser adjustment to 0.8 Watts At a time of 10 seconds after the initiation of assay, were added to the 160 µl of Test Buffer in each well of plate 40 µl of Test Buffer containing 62.5 µM of test substance and 2% DMSO providing a final concentration of 12 µM test substance and DMSO at 0.4% At a time of 75 seconds after the initiation of assay, 50 µl of Test Buffer containing 6 mM CaCl2 at 200 µm present in each well for produce a final concentration of Ca 2+ of 2.0 mM, and a final concentration of test substance of 10 nM. The intensity relative fluorescence (excitation λ = 488 nm / emission λ = 510 nM) is monitored at time intervals relevant throughout the test period to measure the activation and / or inhibition of the receptor.

A modo de ilustración, 1,2,4-oxalato anteriormente descrito, designado "B21" (véase ejemplo 3), tuvo un valor CI_{50} de 43 nM en relación a CaR/mGluR_{54} y un valor CI_{50} de 121 nm sobre el receptor nativo, mGluR_{5d}. Un 1,3-oxazol correspondiente, designado "B52" (véase el ejemplo 7), se encontró que es equipotente sobre la quimera CaR/mGluR_{5d}, con un valor CI_{50} de 45 nM, pero mostró potencia incrementada sobre el receptor nativo GluR_{5d}, con un valor CI_{50} de 74 nM.As an illustration, 1,2,4-oxalate described above, designated "B21" (see example 3), had an IC 50 value of 43 nM in ratio to CaR / mGluR 54 and an IC 50 value of 121 nm over the native receptor, mGluR5d. 1,3-oxazole corresponding, designated "B52" (see example 7), is found that it is equipotent on the chimera CaR / mGluR_ {5d}, with an IC 50 value of 45 nM, but showed increased power over the native GluR5d receptor, with an IC50 value of 74 nM.

Claims (14)

1. Un compuesto seleccionado de1. A compound selected from a) un compuesto de fórmula II:a) a compound of formula II: 
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5454 
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en el queat that X e Y son N,X and Y are N, Z es O;Z is O; Ar^{1} es 2-piridilo y Ar^{2} es fenilo, en el que al menos uno de los restos Ar^{1} y Ar^{2} se sustituye con uno o más restos seleccionados del grupo que consta de -F, -Cl, -Br, -I, -SR, -SOR, -SO_{2}R, -SO_{2}NRR', -OCOR, -OCONRR', -NRCOR', -NRCO_{2}R', -CN, -CO_{2}R, -CONRR', -C(O)R, -CH(OR)R', -CH_{2}(OR), y -R;Ar1 is 2-pyridyl and Ar2 it is phenyl, wherein at least one of the residues Ar 1 and Ar 2 it is replaced with one or more remains selected from the group consisting of -F, -Cl, -Br, -I, -SR, -SOR, -SO 2 R, -SO 2 NRR ', -OCOR, -OCONRR ', -NRCOR', -NRCO_ {2} R ', -CN, -CO_ {2} R, -CONRR', -C (O) R, -CH (OR) R ', -CH_ {(}), and -R; en el que R o R' se selecciona del grupo que consta de H, CF_{3}, alquilo(C_{1}-C_{10}), cicloalquilo, alquilarilo, heterocicloalquilo, arilo y donde R y R' pueden combinarse para formar un anillo,in which R or R 'is selected from the group that consists of H, CF 3, (C 1 -C 10) alkyl, cycloalkyl, alkylaryl, heterocycloalkyl, aryl and where R and R 'can combine to form a ring, con la condición de que el compuesto no sea 3-(2-piridil)-5-(2-clorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-fenil-1,3,4-oxadiazol, o 3-(2-piridil)-5-[3-(trifluorometil)fenil]-1,24-oxadiazol; owith the proviso that the compound is not 3- (2-pyridyl) -5- (2-chlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5-phenyl-1,3,4-oxadiazole, or 3- (2-pyridyl) -5- [3- (trifluoromethyl) phenyl] -1,24-oxadiazole; or b) 3-(2-piridil)-5-[3-(trifluorometoxi)fenil]-1,2,4-oxadiazol,b) 3- (2-pyridyl) -5- [3- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole, 3-(2-piridil)-5-(2,3-difluorofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (2,3-difluorophenyl) -1,2,4-oxadiazole, 3-(2-piridil)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3-(5-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (5-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol,3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3-(2-piridil)-5-(3-nitrofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3-nitrophenyl) -1,2,4-oxadiazole, 2-[3-clorofenil]-4-[piridin-2-il]-1,3-oxazol,2- [3-chlorophenyl] -4- [pyridin-2-yl] -1,3-oxazole, 2-(3,5-diclorofenil)-4-[piridin-2-il]-1,3-oxazol,2- (3,5-dichlorophenyl) -4- [pyridin-2-yl] -1,3-oxazole, 2-(3-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (2-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-metilfenil)-4-(2-piridil)-1,3-oxazol,2- (3-methylphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-trifluorometoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-Trifluoromethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,3-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3,5-dimetoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,3-diclorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-dichlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cloro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-fluoro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-fluoro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cloro-5-fluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-fluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-cloropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-chloropyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole, 2-(3-ciano-5-fluorofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyano-5-fluorophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(3-fluoropirid-3-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-fluoropyrid-3-yl) -1,3-oxazole, 2-(3,5-dimetoxifenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(3-cloro-5-trifluorometilpirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-chloro-5-trifluoromethylpyrid-2-yl) -1,3-oxazole, 2-(5-cloro-2-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Chloro-2-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2-cloro-5-metiltiofenil)-4-(2-piridil)-1,3-oxazol,2- (2-Chloro-5-methylthiophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(5-bromo-5-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Bromo-5-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-clorofenil)-4-(piridin-2-il)-1,3-oxazol,2- (3-chlorophenyl) -4- (pyridin-2-yl) -1,3-oxazole, 2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-nitrofenil)-4-(2-piridil)-1,3-oxazol,2- (3-nitrophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-bromofenil)-4-(2-piridil)-1,3-oxazol, o2- (3-bromophenyl) -4- (2-pyridyl) -1,3-oxazole, or una sal farmacéuticamente aceptable de los mismos.a pharmaceutically acceptable salt of same. 2. El compuesto de la reivindicación 1, en el que Ar^{2} se sustituye con uno o más restos seleccionados del grupo que consta de CF_{3}, Cl, F, Br, CH_{3}, SCH_{3}, y CN.2. The compound of claim 1, wherein Ar2 is replaced with one or more moieties selected from the group consisting of CF_ {3}, Cl, F, Br, CH_ {3}, SCH_ {3}, and CN. 3. El compuesto de la reivindicación 1, en el que Ar^{1} se sustituye con uno o más restos seleccionados del grupo que consta de CF_{3}, F, y Cl.3. The compound of claim 1, wherein Ar1 is replaced with one or more moieties selected from the group consisting of CF_ {3}, F, and Cl. 4. El compuesto de la reivindicación 1, seleccionándose dicho compuesto del grupo que consta de 3-(2-piridil)-5-(3,5-diclorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-clorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-metilfenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,5-difluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3,5-difluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,3-diclorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-cloro-5-cianofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-fluoro-5-cianofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-cloro-5-fluorofenil)-1,2,4-oxadiazol, 3-(3-fluoropirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(5-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol, 3-(5-fluroropirid-2-il)-5-(3-ciano-5-fluorofenil)-1,2,4-oxadiazol, 3-(3-fluroropirid-2-il)-5-(3-
cianofenil)-1,2,4-oxadiazol, 3-(3-cloro-5-trifluorometilpirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(5-cloro-2-metoxifenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2-cloro-5-metiltiofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,5,6-trifluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(2,5,6-trifluorofenil)-1,2,4-oxadiazol, 3-(2-piridil)-5-(3-bromofenil)-
1,2,4-oxadiazol y sales farmacéuticamente aceptables de los mismos.4. The compound of claim 1, said compound being selected from the group consisting of 3- (2-pyridyl) -5- (3,5-dichlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-chlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-methylphenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5 - (2,5-Difluorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3,5-difluorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (2,3-dichlorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-Chloro-5-cyanophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (3-fluoro-5-cyanophenyl) -1,2,4-oxadiazole, 3 - (2-pyridyl) -5- (3-chloro-5-fluorophenyl) -1,2,4-oxadiazole, 3- (3-fluoropyrid-2-yl) -5- (3-cyanophenyl) -1,2 , 4-oxadiazole, 3- (5-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3- (5-fluroropyrid-2-yl) -5- ( 3-cyano-5-fluorophenyl) -1,2,4-oxadiazole, 3- (3-fluroropyrid-2-yl) -5- (3-
cyanophenyl) -1,2,4-oxadiazole, 3- (3-chloro-5-trifluoromethylpyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (5-chloro-2-methoxyphenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (2-chloro-5-methylthiophenyl) -1,2,4-oxadiazole, 3 - (2-pyridyl) -5- (2,5,6-trifluorophenyl) -1,2,4-oxadiazole, 3- (2-pyridyl) -5- (2,5,6-trifluorophenyl) -1.2 , 4-oxadiazole, 3- (2-pyridyl) -5- (3-bromophenyl) -
1,2,4-oxadiazole and pharmaceutically acceptable salts thereof. 
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5. Una composición farmacéutica que comprende un compuesto selecionado de5. A pharmaceutical composition comprising a selected compound of a) un compuesto de fórmula II:a) a compound of formula II: 5555 en el que X e Y son N,in which X and Y are N, Z es O;Z is O; Ar^{1} es 2-piridilo y Ar^{2} es fenilo, en el que al menos uno de los restos Ar^{1} y Ar^{2} se sustituye con uno o más restos seleccionados del grupo que consta de -F, -Cl, -Br, -I, -SR, -SOR, -SO_{2}R, -SO_{2}NRR', -OCOR, -OCONRR', -NRCOR', -NRCO_{2}R', -CN, -CO_{2}R, -CONRR', -C(O)R, -CH(OR)R', -CH_{2}(OR), y -R;Ar1 is 2-pyridyl and Ar2 it is phenyl, wherein at least one of the residues Ar 1 and Ar 2 it is replaced with one or more remains selected from the group consisting of -F, -Cl, -Br, -I, -SR, -SOR, -SO 2 R, -SO 2 NRR ', -OCOR, -OCONRR ', -NRCOR', -NRCO_ {2} R ', -CN, -CO_ {2} R, -CONRR', -C (O) R, -CH (OR) R ', -CH_ {(}), and -R; en el que R o R' se selecciona del grupo que consta de H, CF_{3}, alquilo(C_{1}-C_{10}), cicloalquilo, alquilarilo, heterocicloalquilo, arilo y donde R y R' pueden combinarse para formar un anillo,in which R or R 'is selected from the group that consists of H, CF 3, (C 1 -C 10) alkyl, cycloalkyl, alkylaryl, heterocycloalkyl, aryl and where R and R 'can combine to form a ring, con la condición de que el compuesto no sea 3-(2-piridil)-5-(2-clorofenil)-1,2,4-oxadiazol, o 3-(2-piridil)-5-[3-(trifluorometil)fenil]-1,24-oxadiazol; owith the proviso that the compound is not 3- (2-pyridyl) -5- (2-chlorophenyl) -1,2,4-oxadiazole, or 3- (2-pyridyl) -5- [3- (trifluoromethyl) phenyl] -1,24-oxadiazole; or b) 3-(2-piridil)-5-[3-(trifluorometoxi)fenil]-1,2,4-oxadiazol,b) 3- (2-pyridyl) -5- [3- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole, 3-(2-piridil)-5-(2,3-difluorofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (2,3-difluorophenyl) -1,2,4-oxadiazole, 3-(2-piridil)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3-(5-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (5-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol,3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3-(2-piridil)-5-(3-nitrofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3-nitrophenyl) -1,2,4-oxadiazole, 2-[3-clorofenil]-4-[piridin-2-il]-1,3-oxazol,2- [3-chlorophenyl] -4- [pyridin-2-yl] -1,3-oxazole, 2-(3,5-diclorofenil)-4-[piridin-2-il]-1,3-oxazol,2- (3,5-dichlorophenyl) -4- [pyridin-2-yl] -1,3-oxazole, 2-(3-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (2-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-metilfenil)-4-(2-piridil)-1,3-oxazol,2- (3-methylphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-trifluorometoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-Trifluoromethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,3-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3,5-dimetoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,3-diclorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-dichlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cloro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-fluoro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-fluoro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cloro-5-fluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-fluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-cloropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-chloropyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole, 2-(3-ciano-5-fluorofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyano-5-fluorophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(3-fluoropirid-3-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-fluoropyrid-3-yl) -1,3-oxazole, 2-(3,5-dimetoxifenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(3-cloro-5-trifluorometilpirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-chloro-5-trifluoromethylpyrid-2-yl) -1,3-oxazole, 2-(5-cloro-2-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Chloro-2-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2-cloro-5-metiltiofenil)-4-(2-piridil)-1,3-oxazol,2- (2-Chloro-5-methylthiophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(5-bromo-5-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Bromo-5-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-clorofenil)-4-(piridin-2-il)-1,3-oxazol,2- (3-chlorophenyl) -4- (pyridin-2-yl) -1,3-oxazole, 2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-nitrofenil)-4-(2-piridil)-1,3-oxazol,2- (3-nitrophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-bromofenil)-4-(2-piridil)-1,3-oxazol, o2- (3-bromophenyl) -4- (2-pyridyl) -1,3-oxazole, or una sal farmacéuticamente aceptable de los mismos;a pharmaceutically acceptable salt of themselves; y un excipiente farmacéuticamente aceptable.and a pharmaceutically acceptable excipient. 6. La composición de la reivindicación 5, en la que Ar^{2} se sustituye con uno o más restos seleccionados del grupo que consta de CF_{3}, Cl, F, Br, CH_{3}, CN, y SCH_{3}.6. The composition of claim 5, in the that Ar2 is replaced with one or more moieties selected from the group consisting of CF 3, Cl, F, Br, CH 3, CN, and SCH_ {3}. 7. La composición de la reivindicación 5, en la que Ar^{1} se sustituye con uno o más restos seleccionados del grupo que consta de CF_{3}, F, y Cl.7. The composition of claim 5, in the that Ar1 is replaced with one or more moieties selected from the group consisting of CF_ {3}, F, and Cl. 8. Uso de una cantidad farmacéuticamente aceptable de un compuesto seleccionado de8. Use of a quantity pharmaceutically acceptable of a compound selected from a) un compuesto de fórmula II:a) a compound of formula II: 
         \vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
5656 en el que X e Y son N,in which X and Y are N, Z es O;Z is O; Ar^{1} es 2-piridilo y Ar^{2} es fenilo, en el que al menos uno de los restos Ar^{1} y Ar^{2} se sustituye con uno o más restos seleccionados del grupo que consta de -F, -Cl, -Br, -I, -SR, -SOR, -SO_{2}R, -SO_{2}NRR', -OCOR, -OCONRR', -NRCOR', -NRCO_{2}R', -CN, -CO_{2}R, -CONRR', -C(O)R, -CH(OR)R', -CH_{2}(OR), y -R;Ar1 is 2-pyridyl and Ar2 it is phenyl, wherein at least one of the residues Ar 1 and Ar 2 it is replaced with one or more remains selected from the group consisting of -F, -Cl, -Br, -I, -SR, -SOR, -SO 2 R, -SO 2 NRR ', -OCOR, -OCONRR ', -NRCOR', -NRCO_ {2} R ', -CN, -CO_ {2} R, -CONRR', -C (O) R, -CH (OR) R ', -CH_ {(}), and -R; en el que R o R' se selecciona del grupo que consta de H, CF_{3}, alquilo(C_{1}-C_{10}), cicloalquilo, alquilarilo, heterocicloalquilo, arilo y donde R y R' pueden combinarse para formar un anillo,in which R or R 'is selected from the group that consists of H, CF 3, (C 1 -C 10) alkyl, cycloalkyl, alkylaryl, heterocycloalkyl, aryl and where R and R 'can combine to form a ring, con la condición de que el compuesto no sea 3-(2-piridil)-5-(2-clorofenil)-1,2,4-oxadiazol, o 3-(2-piridil)-5-[3-(trifluorometil)fenil]-1,24-oxadiazol; owith the proviso that the compound is not 3- (2-pyridyl) -5- (2-chlorophenyl) -1,2,4-oxadiazole, or 3- (2-pyridyl) -5- [3- (trifluoromethyl) phenyl] -1,24-oxadiazole; or b) 3-(2-piridil)-5-[3-(trifluorometoxi)fenil]-1,2,4-oxadiazol,b) 3- (2-pyridyl) -5- [3- (trifluoromethoxy) phenyl] -1,2,4-oxadiazole, 3-(2-piridil)-5-(2,3-difluorofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (2,3-difluorophenyl) -1,2,4-oxadiazole, 3-(2-piridil)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3-(5-fluoropirid-2-il)-5-(3,5-dimetoxifenil)-1,2,4-oxadiazol,3- (5-fluoropyrid-2-yl) -5- (3,5-dimethoxyphenyl) -1,2,4-oxadiazole, 3-(5-metoxipirid-2-il)-5-(3-cianofenil)-1,2,4-oxadiazol,3- (5-methoxypyrid-2-yl) -5- (3-cyanophenyl) -1,2,4-oxadiazole, 3-(2-piridil)-5-(3-nitrofenil)-1,2,4-oxadiazol,3- (2-pyridyl) -5- (3-nitrophenyl) -1,2,4-oxadiazole, 2-[3-clorofenil]-4-[piridin-2-il]-1,3-oxazol,2- [3-chlorophenyl] -4- [pyridin-2-yl] -1,3-oxazole, 2-(3,5-diclorofenil)-4-[piridin-2-il]-1,3-oxazol,2- (3,5-dichlorophenyl) -4- [pyridin-2-yl] -1,3-oxazole, 2-(3-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2-clorofenil)-4-(2-piridil)-1,3-oxazol,2- (2-chlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-metilfenil)-4-(2-piridil)-1,3-oxazol,2- (3-methylphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-trifluorometoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3-Trifluoromethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,3-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3,5-difluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-difluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3,5-dimetoxifenil)-4-(2-piridil)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,3-diclorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,3-dichlorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cloro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-fluoro-5-cianofenil)-4-(2-piridil)-1,3-oxazol,2- (3-fluoro-5-cyanophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cloro-5-fluorofenil)-4-(2-piridil)-1,3-oxazol,2- (3-Chloro-5-fluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-cloropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-chloropyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole, 2-(3-ciano-5-fluorofenil)-4-(5-fluoropirid-2-il)-1,3-oxazol,2- (3-cyano-5-fluorophenyl) -4- (5-fluoropyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(3-fluoropirid-3-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-fluoropyrid-3-yl) -1,3-oxazole, 2-(3,5-dimetoxifenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3,5-dimethoxyphenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(5-metoxipirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (5-methoxypyrid-2-yl) -1,3-oxazole, 2-(3-cianofenil)-4-(3-cloro-5-trifluorometilpirid-2-il)-1,3-oxazol,2- (3-cyanophenyl) -4- (3-chloro-5-trifluoromethylpyrid-2-yl) -1,3-oxazole, 2-(5-cloro-2-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Chloro-2-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2-cloro-5-metiltiofenil)-4-(2-piridil)-1,3-oxazol,2- (2-Chloro-5-methylthiophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(5-bromo-5-metoxifenil)-4-(2-piridil)-1,3-oxazol,2- (5-Bromo-5-methoxyphenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-clorofenil)-4-(piridin-2-il)-1,3-oxazol,2- (3-chlorophenyl) -4- (pyridin-2-yl) -1,3-oxazole, 2-(2,5,6-trifluorofenil)-4-(2-piridil)-1,3-oxazol,2- (2,5,6-trifluorophenyl) -4- (2-pyridyl) -1,3-oxazole, 2-(3-nitrofenil)-4-(2-piridil)-1,3-oxazol, o2- (3-nitrophenyl) -4- (2-pyridyl) -1,3-oxazole, or 2-(3-bromofenil)-4-(2-piridil)-1,3-oxazol;2- (3-bromophenyl) -4- (2-pyridyl) -1,3-oxazole; con la condición de que el compuesto no sea 3-(2-piridil)-5-(2-clorofenl)-1,2,4-oxadiazol, para la preparación de un médicamente para el tratamiento de enfermedades asociadas con receptores metabotrópicos de glutamato.on the condition that the compound not be 3- (2-pyridyl) -5- (2-chlorophenl) -1,2,4-oxadiazole, for the preparation of a medically for the treatment of diseases associated with metabotropic receptors of glutamate. 9. El uso de acuerdo con la reivindicación 8, en el que Ar^{2} se sustituye con uno o más restos seleccionados del grupo que consta de CF_{3}, Cl, F, Br, CH_{3}, CN, y SCH_{3}.9. The use according to claim 8, in which Ar2 is replaced with one or more moieties selected from the group consisting of CF 3, Cl, F, Br, CH 3, CN, and SCH_ {3}. 10. El uso de acuerdo con la reivindicación 10, en el que Ar^{1} se sustituye con uno o más restos seleccionados del grupo que consta de CF_{3}, F, y Cl.10. The use according to claim 10, wherein Ar 1 is substituted with one or more selected moieties of the group consisting of CF_ {3}, F, and Cl. 11. El uso de acuerdo con la reivindicación 8, en el que la enfermedad asociada con los receptores metabotrópicos de glutamato es una enfermedad o trastorno neurológico.11. The use according to claim 8, in which the disease associated with metabotropic receptors of Glutamate is a disease or neurological disorder. 12. El uso de acuerdo con la reivindicación 8, en el que la enfermedad asociada con los receptores metabotrópicos de glutamato es una enfermedad psiquiátrica.12. The use according to claim 8, in which the disease associated with metabotropic receptors of Glutamate is a psychiatric disease. 13. El uso de acuerdo con la reivindicación 8, en el que la enfermedad o trastorno se selecciona del grupo que consta de apoplejía, traumatismo en la cabeza, daño anóxico, daño isquémico, hipoglicemia, epilepsia, dolor, dolores de cabeza migrañosos, enfermedad de Parkinson, demencia senil, Corea de Huntington y enfermedad de Alzheimer.13. The use according to claim 8, in the one that the disease or disorder is selected from the group that consists from stroke, head trauma, anoxic damage, damage ischemic, hypoglycemia, epilepsy, pain, headaches Migraine, Parkinson's disease, senile dementia, Korea's Huntington and Alzheimer's disease. 14. El uso de acuerdo con la reivindicación 8, en el que la enfermedad o trastorno se selecciona del grupo que consta de esquizofrenia y depresión.14. The use according to claim 8, in the one that the disease or disorder is selected from the group that consists of schizophrenia and depression.
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